Huntington's Disease References: 2003
Abbruzzese, G. and A. Berardelli (2003). "Sensorimotor integration in movement disorders." Mov Disord 18(3): 231-40.
Although current knowledge attributes movement disorders to a dysfunction of the basal ganglia-motor cortex circuits, abnormalities in the peripheral afferent inputs or in their central processing may interfere with motor program execution. We review the abnormalities of sensorimotor integration described in the various types of movement disorders. Several observations, including those of parkinsonian patients' excessive reliance on ongoing visual information during movement tasks, suggest that proprioception is defective in Parkinson's disease (PD). The disturbance of proprioceptive regulation, possibly related to the occurrence of abnormal muscle-stretch reflexes, might be important for generating hypometric or bradykinetic movements. Studies with somatosensory evoked potentials (SEPs), prepulse inhibition, and event-related potentials support the hypothesis of central abnormalities of sensorimotor integration in PD. In Huntington's disease (HD), changes in SEPs and long-latency stretch reflexes suggest that a defective gating of peripheral afferent input to the brain might impair sensorimotor integration in cortical motor areas, thus interfering with the processing of motor programs. Defective motor programming might contribute to some features of motor impairment in HD. Sensory symptoms are frequent in focal dystonia and sensory manipulation can modify the dystonic movements. In addition, specific sensory functions (kinaesthesia, spatial-temporal discrimination) can be impaired in patients with focal hand dystonia, thus leading to a "sensory overflow." Sensory input may be abnormal and trigger focal dystonia, or defective "gating" may cause an input-output mismatch in specific motor programs. Altogether, several observations strongly support the idea that sensorimotor integration is impaired in focal dystonia. Although elemental sensation is normal in patients with tics, tics can be associated with sensory phenomena. Some neurophysiological studies suggest that an altered "gating" mechanism also underlies the development of tics. This review underlines the importance of abnormal sensorimotor integration in the pathophysiology of movement disorders. Although the physiological mechanism remains unclear, the defect is of special clinical relevance in determining the development of focal dystonia.
Aron, A. R., F. Schlaghecken, et al. (2003). "Inhibition of subliminally primed responses is mediated by the caudate and thalamus: evidence from functional MRI and Huntington's disease." Brain 126(Pt 3): 713-23.
Masked prime tasks have shown that sensory information that has not been consciously perceived can nevertheless trigger the preactivation of a motor response. Automatic inhibitory control processes prevent such response tendencies from interfering with behaviour. The present study investigated the possibility that these inhibitory control processes are mediated by a cortico-striatal-pallidal-thalamic pathway by using a masked prime task with Huntington's disease patients (Experiment 1) and with healthy volunteers in a functional MRI (fMRI) study (Experiment 2). In the masked prime task, clearly visible left- or right-pointing target arrows are preceded by briefly presented and subsequently masked prime arrows. Participants respond quickly with a left or right key-press to each target. Trials are either compatible (prime and target pointing in the same direction) or incompatible (prime and target pointing in different directions). Prior behavioural and electrophysiological results show that automatic inhibition of the initially primed response tendency is reflected in a 'negative compatibility effect' (faster reaction times for incompatible trials than for compatible trials), and is shown to consist of three distinct processes (prime activation, response inhibition and response conflict) occurring within 300 ms. Experiment 1 tested the hypothesis that lesions of the striatum would interrupt automatic inhibitory control by studying early-stage Huntington's disease patients. Findings supported the hypothesis: there was a bimodal distribution for patients, with one-third (choreic) showing disinhibition, manifested as an absent negative compatibility effect, and two-thirds (non-choreic) showing excessive inhibition, manifested as a significantly greater negative compatibility effect than that in controls. Experiment 2 used fMRI and a region of interest (ROI) template-based method to further test the hypothesis that structures of the striatal-pallidal-thalamic pathway mediate one or more of the processes of automatic inhibitory control. Neither prime activation nor response conflict significantly engaged any ROIs, but the response inhibition process led to significant modulation of both the caudate and thalamus. Taken together, these experiments indicate a causal role for the caudate nucleus and thalamus in automatic inhibitory motor control, and the results are consistent with performance of the task requiring both direct and indirect striatal-pallidal-thalamic pathways. The finding that Huntington's disease patients with greater chorea were disinhibited is consistent with the theory that chorea arises from selective degeneration of striatal projections to the lateral globus pallidus, while the exaggerated inhibitory effect for patients with little or no chorea may be due to additional degeneration of projections to the medial globus pallidus.
Baylin, A., E. K. Kabagambe, et al. (2003). "Adipose tissue alpha-linolenic acid and nonfatal acute myocardial infarction in Costa Rica." Circulation 107(12): 1586-91.
BACKGROUND: Alpha-linolenic acid may protect against cardiovascular disease. We examined the association between adipose tissue alpha-linolenic acid and nonfatal acute myocardial infarction (MI) in a population-based case-control study in Costa Rica. METHODS AND RESULTS: The 482 case patients with a first nonfatal acute MI and 482 population control subjects were matched by age, sex, and area of residence. Fatty acids were assessed by gas-liquid chromatography in adipose tissue samples collected from all subjects. ORs and 95% CIs were calculated from multivariate conditional logistic regression models. Subjects in the top quintiles of adipose tissue alpha-linolenic acid had a lower risk of MI than those in the lowest quintile: OR (95% CI), 1.00; 0.80 (0.52 to 1.24); 0.53 (0.34 to 0.82); 0.44 (0.28 to 0.67); and 0.37 (0.24 to 0.59); test for trend, P<0.0001. This association was strengthened after adjustment for established MI risk factors, including smoking, physical activity, income, and adipose tissue linoleic acid and trans fatty acids (OR for the top versus lowest quintile, 0.23; 95% CI, 0.10 to 0.50; test for trend, P<0.0001). Further adjustment for the intake of saturated fat, fiber, alcohol, and vitamin E did not change this association (OR for the top versus lowest quintile, 0.23; 95% CI, 0.10 to 0.55; test for trend, P<0.0001). CONCLUSIONS: The inverse association observed between alpha-linolenic acid and nonfatal acute MI suggests that consumption of vegetable oils rich in alpha-linolenic acid confers important protection against cardiovascular disease.
Beal, M. F. (2003). "Bioenergetic approaches for neuroprotection in Parkinson's disease." Ann Neurol 53(3 Suppl 1): S39-48.
There is considerable evidence suggesting that mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Parkinson's disease (PD). This possibility has been strengthened by recent studies in animal models, which have shown that a selective inhibitor of complex I of the electron transport gene can produce an animal model that closely mimics both the biochemical and histopathological findings of PD. Several agents are available that can modulate cellular energy metabolism and that may exert antioxidative effects. There is substantial evidence that mitochondria are a major source of free radicals within the cell. These appear to be produced at both the iron-sulfur clusters of complex I as well as the ubiquinone site. Agents that have shown to be beneficial in animal models of PD include creatine, coenzyme Q(10), Ginkgo biloba, nicotinamide, and acetyl-L-carnitine. Creatine has been shown to be effective in several animal models of neurodegenerative diseases and currently is being evaluated in early stage trials in PD. Similarly, coenzyme Q(10) is also effective in animal models and has shown promising effects both in clinical trials of PD as well as in clinical trials in Huntington's disease and Friedreich's ataxia. Many other agents show good human tolerability. These agents therefore are promising candidates for further study as neuroprotective agents in PD. Ann Neurol 2003;53 (suppl 3):S39-S48
Bilney, B., M. E. Morris, et al. (2003). "Effectiveness of physiotherapy, occupational therapy, and speech pathology for people with Huntington's disease: a systematic review." Neurorehabil Neural Repair 17(1): 12-24.
This review provides a summary of the current literature examining the outcomes of physiotherapy, occupational therapy, and speech pathology interventions for people with Huntington's disease. The literature was retrieved via a systematic search using a combination of key words that included Huntington's disease, physiotherapy, occupational therapy, and speech pathology. The electronic databases for Medline, Embase, CINAHL, Cochrane Controlled Trials Register, and PEDro were searched up to May 2002. Articles meeting the review criteria were graded for study type and rated for quality using checklists to assess study validity and methodology. The majority of articles that examined therapy outcomes for people with Huntington's disease were derived from observational studies of low methodological quality. A low level of evidence exists to support the use of physiotherapy for addressing impairments of balance, muscle strength, and flexibility. There was a small amount of evidence to support the use of speech pathology for the management of eating and swallowing disorders. The current evidence is insufficient to make strong recommendations regarding the usefulness of physiotherapy, occupational therapy, or speech pathology for people with Huntington's disease. There is further need for therapy outcomes research in Huntington's disease so that clinicians may use evidence-based practice to assist clinical decision making.
Bing, R. J. (2003). "Cyclooxygenase-2 inhibitors: is there an association with coronary or renal events?" Curr Atheroscler Rep 5(2): 114-7.
The article is concerned with the effects of specific cyclooxygenase-2 (COX-2) inhibitors and their relationship to thrombotic cardiovascular events and to renal disease. Clinical and experimental aspects of COX-2-specific inhibitors are cited. A COX-2 inhibitor, celecoxib, interferes with myocardial prostacyclin production and also produces hypertension. Data have shown that in animal experiments, celecoxib also lowers myocardial prostaglandin concentration but fails to inhibit thromboxane concentration to the same degree. In the kidney, celecoxib can result in glomerular and interstitial nephritis or papillary necrosis. As in infarcted heart muscle, the COX-2-specific inhibitor celecoxib causes a significant decline in prostaglandin in the renal medulla. It was concluded from both clinical and experimental findings that COX-2 inhibitors can cause thrombotic cardiovascular events as well as renal disease. For these reasons, care should be exercised in administering specific COX-2 inhibitors to patients with pre-existing cardiac or renal disease.
Bonelli, R. M., G. Niederwieser, et al. (2003). "Zotepine in Huntington's disease." Hum Psychopharmacol 18(3): 227-9.
The authors report a patient with Huntington's disease (HD) presenting with severe chorea. The motor scale of the unified HD rating scale (UHDRS-I) revealed 81 points. Motor function clearly improved with zotepine, until she reached an UHDRS-I of 34 points on day 7 of treatment. The patient was stable for at least 12 weeks. The improvement includes all seven categories of the UHDRS-I, especially chorea, gait and oral function. This is the first description of zotepine in HD. Our findings suggest that zotepine is useful in the treatment of HD chorea. Controlled trials of its use in HD would be welcome.
Bonelli, R. M. (2003). "Mirtazapine in suicidal Huntington's disease." Ann Pharmacother 37(3): 452.
Bonelli, R. M., C. Heuberger, et al. (2003). "Minocycline for Huntington's disease: An open label study." Neurology 60(5): 883-4.
Carella, F., M. Bressanelli, et al. (2003). "A study of arm movements in Huntington's disease under visually controlled and blindfolded conditions." Neurol Sci 23(6): 287-93.
The so-called bradykinesia of Huntington's disease (HD) seems not due to reduced movement speed alone but may also be task-dependent. We therefore investigated the influence of visual control on the ability of HD patients to perform a motor task. Ten HD patients, never treated with neuroleptic drugs and with mild functional impairment in activities of daily living, performed the task blindfolded and not blindfolded, as did 10 age- and education-matched healthy controls. The task was to use the dominant hand to trace out the contours of a 20x20 cm square in a clockwise direction, pausing at each corner. The square was marked on the table at which the subject sat. Accuracy was stressed rather than speed. A videocamerabased system recorded movement trajectories, from which kinematic and error parameters were derived. Patients and controls moved at comparable speeds but patients took longer to complete the task due to more curvilinear and hence longer trajectories.Patients spent more time in the deceleration phase of the movement, and in the blindfold condition had more variable movements as indicated by greater error variability scores. Correlation analysis showed that kinematic parameters in patients did not correlate with involuntary movement scores. These findings indicate that abnormalities of motor control are present in HD when movement accuracy (and not velocity) is required. HD patients are more dependent on visual control than normal subjects.
Cattaneo, E. (2003). "Dysfunction of wild-type huntingtin in Huntington disease." News Physiol Sci 18: 34-7.
Huntingtin is the protein involved in Huntington disease (HD), an inherited neurodegenerative disease. Research activities have focused on the abnormal functions of mutant huntingtin. However, recent results indicate that wild-type huntingtin has important activities in brain neurons, suggesting that loss of these activities may play a role in HD.
Caviness, J. N. (2003). "Myoclonus and neurodegenerative disease-what's in a name?" Parkinsonism Relat Disord 9(4): 185-92.
Myoclonus is a clinical symptom (or sign) defined as sudden, brief, shock-like, involuntary movements caused by muscular contractions or inhibitions. It may be classified by examination findings, etiology, or physiological characteristics. The main physiological categories for myocolonus are cortical, cortical-subcortical, subcortical, segmental, and peripheral. Neurodegenerative syndromes are potential causes of symptomatic myoclonus. Such syndromes include multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism linked to chromosome 17, Huntington's disease, dentato-rubro-pallido-luysian atrophy, Alzheimer's disease, and Parkinson's disease, and other Lewy body disorders. Each neurodegenerative syndrome can have overlapping as well as distinctive clinical neurophysiological properties. However, claims of differentiating between neurodegenerative disorders by using the presence or absence of small amplitude distal action myclonus appear unwarranted. When the myoclonus is small and repetitive, it may not be possible to distinguish it from tremor by phenotypic appearance alone. In this case, clinical neurophysiological offers an opportunity to provide greater differentiation of the phenomenon. More study of the myoclonus in neurodegenerative disease will lead to a better understanding of the processes that cause phenotypic variability among these disorders.
Cepeda, C., R. S. Hurst, et al. (2003). "Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease." J Neurosci 23(3): 961-9.
Alterations in the corticostriatal pathway may precede symptomatology and striatal cell death in Huntington's disease (HD) patients. Here we examined spontaneous EPSCs in striatal medium-sized spiny neurons in slices from a mouse model of HD (R6/2). Spontaneous EPSC frequency was similar in young (3-4 weeks) transgenics and controls but decreased significantly in transgenics when overt behavioral symptoms began (5-7 weeks) and was most pronounced in severely impaired transgenics (11-15 weeks). These differences were maintained after bicuculline or tetrodotoxin, indicating they were specific to glutamatergic input and likely presynaptic in origin. Decreases in presynaptic and postsynaptic protein markers, synaptophysin and postsynaptic density-95, occurred in 11-15 week R6/2 mice, supporting the electrophysiological results. Furthermore, isolated, large-amplitude synaptic events (>100 pA) occurred more frequently in transgenic animals, particularly at 5-7 weeks, suggesting additional dysregulation of cortical inputs. Large events were blocked by tetrodotoxin, indicating a possible cortical origin. Addition of bicuculline and 4-aminopyridine facilitated the occurrence of large events. Riluzole, a compound that decreases glutamate release, reduced these events. Together, these observations indicate that both progressive and transient alterations occur along the corticostriatal pathway in experimental HD. These alterations are likely to contribute to the selective vulnerability of striatal medium-sized spiny neurons.
Chari, S., S. H. Quraishi, et al. (2003). "Fluoxetine-induced exacerbation of chorea in Huntington's disease? A case report." Pharmacopsychiatry 36(1): 41-3.
Cribbs, D. H., A. Ghochikyan, et al. (2003). "Adjuvant-dependent modulation of T(h)1 and T(h)2 responses to immunization with beta-amyloid." Int Immunol 15(4): 505-514.
The role of adjuvant on the T(h)1 and T(h)2 immune responses to Abeta-immunotherapy (Abeta(42 )peptide) was examined in wild-type mice. Fine epitope analysis with overlapping oligomers of the Abeta(42) sequence identified the 1-15 region as a dominant B cell epitope. The 6-20 peptide was recognized only weakly by antisera from mice administrated with Abeta(42) peptide formulated in complete Freund's adjuvant (CFA), alum or TiterMax Gold (TMG). However, mice immunized with Abeta(42) mixed with QS21 induced a significant antibody response to the 6-20 peptide. The only T cell epitope found was within the 6-28 sequence of Abeta(42). QS21 and CFA induced the strongest humoral response to Abeta, alum was intermediate, and TMG the weakest adjuvant. Analysis of antibody isotypes specific for Abeta indicates that alum induces primarily T(h)2-type immune response, whereas TMG, CFA and QS21 shift the immune responses toward a T(h)1 phenotype. Stimulation of splenocytes from Abeta-immunized mice with Abeta(40) peptide induced strikingly different cytokine expression profiles. QS21 and CFA induced significant IFN-gamma, IL-4 and tumor necrosis factor-alpha expression, whereas alum induced primarily IL-4 production. As T(h)1-type immune responses have been implicated in many autoimmune disorders, whereas T(h)2-type responses have been shown to inhibit autoimmune disease, the choice of adjuvant may be critical for the design of a safe and effective immunotherapy for Alzheimer's disease.
Cristalli, G., C. Lambertucci, et al. (2003). "Medicinal Chemistry of Adenosine A(2A) Receptor Agonists." Curr Top Med Chem 3(4): 387-401.
The search for potent and selective A(2A) adenosine receptor agonists has been particularly fruitful in the early nineties. A series of 2-amino, 2-alkoxy, 2-alkythio-, 2-alkynyl-, and 2-alkenyl-derivatives of adenosine (Ado, 1) and N-ethylcarboxamidoadenosine (NECA, 30) have been synthesized and tested mainly on different model of rat A(1) and A(2A) receptor subtypes. From these studies some ligands, such as CGS 21680 (33), HENECA (42), and (S)-PHPNECA (46b), showed to possess high A(2A) affinity combined with good A(2A) vs A(1) selectivity. More detailed characterization of these ligands at the four cloned human adenosine receptor subtypes revealed that none of the prototypical adenosine receptor agonists exhibits at the same time high affinity and selectivity for the human A(2A)AR subtype. Both NECA and CGS 21680, which are avalaible as radioligands for this subtype, have lower affinity at human than at rat receptor. The 2-alkynylNECA derivatives HENECA an PHPNECA showed high affinity also at human A(3) receptors. In particular, (S)-PHPNECA displayed K(i)s in the low nanomolar range at A(1), A(2A), and A(3)subtypes and an EC(50) of 220 nM at human A(2B) receptor. On the other hand, it is now well known that the coronary vasodilation induced by Ado in different species is mediated by activation of A(2A)AR and a compound capable of producing coronary vasodilation through activation of A(2A)AR, but that is devoid of A(1)- and A(1)-agonist activity would have advantage over Ado for use in myocardial perfusion imaging studies. Other potential therapeutic applications of selective A(2A)AR agonists are as anti-aggregatory, anti-inflammatory, anti-psychotic, and anti-Huntington's disease agents. This review is aimed at presenting a complete overview of the medicinal chemistry development of A(2A) adenosine receptor agonists and at stressing the strong need for more selective ligands at A(2A) human subtype.
Decruyenaere, M., G. Evers-Kiebooms, et al. (2003). "Psychological distress in the 5-year period after predictive testing for Huntington's disease." Eur J Hum Genet 11(1): 30-8.
The paper reports on a 5-year longitudinal study on psychological distress after predictive testing for Huntington's disease (HD) and on correlates of post-test distress. Psychometric tests and questionnaires were used. The tested persons were invited to participate in the follow-up study; the uptake rate was 75% (24 carriers, 33 non-carriers). Three time points were included: baseline, 1 year and 5 years post-test. Five years after the test, mean distress scores of both carriers and non-carriers were within the normal range. Carriers did not differ from non-carriers with regard to mean general distress. Compared to non-carriers, however, carriers had significantly less positive feelings (P<0.001) and were more consciously avoiding HD-related situations and thoughts (P<0.01). These findings reflect the carriers' conscious and unconscious attempt to escape from pessimism and to minimise negative consequences of the test result. Psychological distress 5 years post-test was significantly associated with ego-strength (P<0.05 to P<0.001). Except for intrusion and avoidance, distress was also associated with test motivation (P<0.05 to P<0.01). Compared with baseline level, mean depression, general and specific anxiety had significantly decreased 1 year and 5 years post-test (P<0.05 to 0.01). This evolution was independent of the test result. However, based on test motivation, a subgroup of tested persons having long lasting psychological distress could be identified, also irrespective of test result. Persons who asked the test to get rid of the uncertainty, without being able to specify implications for substantial life areas, had more psychological distress before and after the test than those who wanted the test for specific reasons (P<0.001 to P<0.0001). Moreover, the pattern of post-test anxiety differed over time, depending on the test motivation (P<0.05). The findings suggest that pre- and post-test counselling should pay special attention to persons with lower ego-strength and with an unspecified test motivation, because they are at higher risk for long-term psychological distress, independently of the test result.European Journal of Human Genetics (2002) 11, 30-38. doi:10.1038/sj.ejhg.5200913
Dou, F., W. J. Netzer, et al. (2003). "Chaperones increase association of tau protein with microtubules." Proc Natl Acad Sci U S A 100(2): 721-6.
Molecular chaperones and their functions in protein folding have been implicated in several neurodegenerative diseases, including Parkinson's disease and Huntington's disease, which are characterized by accumulation of protein aggregates (e.g., alpha-synuclein and huntingtin, respectively). These aggregates have been shown in various experimental systems to respond to changes in levels of molecular chaperones suggesting the possibility of therapeutic intervention and a role for chaperones in disease pathogenesis. It remains unclear whether chaperones also play a role in Alzheimer's disease, a neurodegenerative disorder characterized by beta-amyloid and tau protein aggregates. Here, we report an inverse relationship between aggregated tau and the levels of heat shock protein (Hsp)7090 in tau transgenic mouse and Alzheimer's disease brains. In various cellular models, increased levels of Hsp70 and Hsp90 promote tau solubility and tau binding to microtubules, reduce insoluble tau and cause reduced tau phosphorylation. Conversely, lowered levels of Hsp70 and Hsp90 result in the opposite effects. We have also demonstrated a direct association of the chaperones with tau proteins. Our results suggest that up-regulation of molecular chaperones may suppress formation of neurofibrillary tangles by partitioning tau into a productive folding pathway and thereby preventing tau aggregation.
Duan, W., Z. Guo, et al. (2003). "Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice." Proc Natl Acad Sci U S A 100(5): 2911-6.
In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.
El-Guendy, N. and V. M. Rangnekar (2003). "Apoptosis by Par-4 in cancer and neurodegenerative diseases." Exp Cell Res 283(1): 51-66.
Prostate apoptosis response-4 (par-4) is a pro-apoptotic gene identified in prostate cancer cells undergoing apoptosis. Par-4 protein, which contains a leucine zipper domain at the carboxy-terminus, functions as a transcriptional repressor in the nucleus. Par-4 selectively induces apoptosis in androgen-independent prostate cancer cells and Ras-transformed cells but not in androgen-dependent prostate cancer cells or normal cells. Cells that are resistant to apoptosis by Par-4 alone, however, are greatly sensitized by Par-4 to the action of other pro-apoptotic insults such as growth factor withdrawal, tumor necrosis factor, ionizing radiation, intracellular calcium elevation, or those involved in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and stroke. Apoptosis induction by Par-4 involves a complex mechanism that requires activation of the Fas death receptor signaling pathway and coparallel inhibition of cell survival NF-kappaB transcription activity. The unique ability of Par-4 to induce apoptosis in cancer cells but not normal cells and the ability of Par-4 antisense or dominant-negative mutant to abrogate apoptosis in neurodegenerative disease paradigms makes it an appealing candidate for molecular therapy of cancer and neuronal diseases.
Evers, S. and F. Stogbauer (2003). "Genetic association of Huntington's disease and restless legs syndrome? A family report." Mov Disord 18(2): 226-8.
We report on a family with comorbidity of Huntington's disease (HD) and idiopathic restless legs syndrome (RLS). All family members investigated and affected by RLS are also affected by HD, but not vice versa. The association of HD and RLS is discussed with respect to dopaminergic dysfunction.
Fortune, M. T., J. L. Kennedy, et al. (2003). "Anticipation and CAG*CTG Repeat Expansion in Schizophrenia and Bipolar Affective Disorder." Curr Psychiatry Rep 5(2): 145-54.
The genetic contribution to the etiologies of schizophrenia and bipolar affective disorder (BPAD) has been considered for many decades, with twin, family, and adoption studies indicating consistently that the familial clustering of affected individuals is accounted for mainly by genetic factors. Despite the strong evidence for a genetic component, very little is understood about the underlying genetic and molecular mechanisms for schizophrenia and BPAD. In the early 1990s, after the discovery of "dynamic mutation" or "unstable DNA" as a molecular basis for the genetic anticipation observed in Huntington's disease, myotonic dystrophy, and many others, and the recently rediscovered, albeit still controversial, evidence for genetic anticipation in major psychoses, the genetic epidemiology of schizophrenia and BPAD was re-evaluated to demonstrate strong endorsement for the unstable DNA model. Many of the non-Mendelian genetic features of schizophrenia and BPAD could be explained by the behaviour of unstable DNA, and several molecular genetic approaches became available for testing the unstable DNA hypothesis. However, despite promising findings in the mid-1990s, no trinucleotide repeat expansion has yet been identified as a cause of idiopathic schizophrenia or BPAD.
Friedlander, R. M. (2003). "Apoptosis and caspases in neurodegenerative diseases." N Engl J Med 348(14): 1365-75.
Fusco, F. R., A. Martorana, et al. (2003). "Huntingtin distribution among striatal output neurons of normal rat brain." Neurosci Lett 339(1): 53-6.
Huntingtin is the protein whose mutation leads to Huntington's disease (HD). The protein is heterogeneously distributed in the telencephalon, and not consistently correlated with cell vulnerability in HD [Fusco, F.R., Chen, Q., Lamoreaux, W.J., Figueredo-Cardenas, G., Jiao, Y., Coffman, J.A., Surmeier, D.J., Honig, M.G., Carlock, L.R., and Reiner, A., J. Neurosci., 19 (1999) 1189-1202]. The aim of our study was to investigate a possible preferential distribution of huntingtin among the two main striatal output pathways, namely, the striatonigral and the striatopallidal circuit. Dual label immunofluorescence by means of confocal microscopy was used to detect the presence of huntingtin among striatal projection neurons identified by their cellular content of Substance P, Enkephalin, CB1 receptor, and D1a dopamine receptor. Our data showed that striatopallidal neurons co-containing SP and D1a [Surmeier, D.J., Song, W.J., and Yan, Z., J. Neurosci., 16 (1996) 6579-6591] co-localized with huntingtin in a higher proportion than striatonigral neurons.
Gasser, T., S. Bressman, et al. (2003). "State of the art review: molecular diagnosis of inherited movement disorders. Movement Disorders Society task force on molecular diagnosis." Mov Disord 18(1): 3-18.
This review is designed to provide practical help for the clinical neurologist to make appropriate use of the possibilities of molecular diagnosis of inherited movement disorders. Huntington's disease, Parkinson's disease and parkinsonian syndromes, ataxias, Wilson disease, essential tremor, dystonias, and other genetic diseases associated with a variety of movement disorders are considered separately.
Georgiou-Karistianis, N., E. Smith, et al. (2003). "Future directions in research with presymptomatic individuals carrying the gene for Huntington's disease." Brain Res Bull 59(5): 331-8.
Presymptomatic individuals carrying the gene for Huntington's disease (HD) provide researchers with a unique opportunity of learning more about the neuropathophysiology, symptom onset, behavioural functioning, and mediating factors of this fatal disease. In this review, we attempt to demonstrate that research over the last 8 years, since the isolation of the gene, has remained at large controversial. Although we are aware of some of the factors that can influence age at onset and disease progression, we are still unable to determine exactly when an individual will develop HD symptoms, and how fast these symptoms will progress. In an era rapidly advancing with respect to therapeutic intervention that could forestall the onset and progression of HD, systematic research with improved inclusion criteria is paramount. A greater understanding of the time course of the disease would be beneficial not only in monitoring the effectiveness of future treatments, but also in determining the most appropriate time to administer them. Finally, we present various ethical considerations, as well as put forward various recommendations that could assist in better diagnosing preclinical deficits in presymptomatic individuals.
Gines, S., I. S. Seong, et al. (2003). "Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice." Hum Mol Genet 12(5): 497-508.
Defects in gene transcription and mitochondrial function have been implicated in the dominant disease process that leads to the loss of striatal neurons in Huntington's disease (HD). Here we have used precise genetic HD mouse and striatal cell models to investigate the hypothesis that decreased cAMP responsive element (CRE)-mediated gene transcription may reflect impaired energy metabolism. We found that reduced CRE-signaling in Hdh(Q111) striatum, monitored by brain derived neurotrophic factor and phospho-CRE binding protein (CREB), predated inclusion formation. Furthermore, cAMP levels in Hdh(Q111) striatum declined from an early age (10 weeks), and cAMP was significantly decreased in HD postmortem brain and lymphoblastoid cells, attesting to a chronic deficit in man. Reduced CRE-signaling in cultured STHdh(Q111) striatal cells was associated with cytosolic CREB binding protein that mirrored diminished cAMP synthesis. Moreover, mutant cells exhibited mitochondrial respiratory chain impairment, evidenced by decreased ATP and ATP/ADP ratio, impaired MTT conversion and heightened sensitivity to 3-nitropropionic acid. Thus, our findings strongly suggest that impaired ATP synthesis and diminished cAMP levels amplify the early HD disease cascade by decreasing CRE-regulated gene transcription and altering energy dependent processes essential to neuronal cell survival.
Gonzalez-Gonzalez, M. C., M. J. Trujillo, et al. (2003). "Early Huntington disease prenatal diagnosis by maternal semiquantitative fluorescent-PCR." Neurology 60(7): 1214-5.
Gonzalez-Gonzalez, M. C., M. J. Trujillo, et al. (2003). "Huntington disease-unaffected fetus diagnosed from maternal plasma using QF-PCR." Prenat Diagn 23(3): 232-4.
The discovery of fetal DNA in maternal plasma from early pregnancies has led to new opportunities for clinical application. In the last few years there have been numerous reported applications, mainly fetal gender and RhD genotyping. The prenatal diagnosis of some inherited genetic diseases such as Huntington disease is also very frequently required in the prenatal diagnosis routine. We have successfully diagnosed, with a non-invasive procedure, an unaffected HD fetus at the 13th week of gestation using fetal DNA from maternal plasma and the quantitative fluorescent PCR method, which is one of the most sensitive ways to detect fetal DNA in maternal plasma at such an early time of gestation.
Graether, S. P., C. M. Slupsky, et al. (2003). "Freezing of a fish antifreeze protein results in amyloid fibril formation." Biophys J 84(1): 552-7.
Amyloid is associated with a number of diseases including Alzheimer's, Huntington's, Parkinson's, and the spongiform encephalopathies. Amyloid fibrils have been formed in vitro from both disease and nondisease related proteins, but the latter requires extremes of pH, heat, or the presence of a chaotropic agent. We show, using fluorescence spectroscopy, electron microscopy, and solid-state NMR spectroscopy, that the alpha-helical type I antifreeze protein from the winter flounder forms amyloid fibrils at pH 4 and 7 upon freezing and thawing. Our results demonstrate that the freezing of some proteins may accelerate the formation of amyloid fibrils.
Green, M. J. and J. R. Botkin (2003). ""Genetic Exceptionalism" in Medicine: Clarifying the Differences between Genetic and Nongenetic Tests." Ann Intern Med 138(7): 571-5.
Predictive genetic tests are now available for assessing susceptibility to a variety of conditions, including breast and colon cancer, hemochromatosis, and Alzheimer and Huntington disease. Much controversy surrounds the application of these tests, stemming from their similarities to and differences from other tests commonly used in asymptomatic persons. Some have argued that genetic tests are unique and therefore justify special consideration with regard to informed consent and privacy. This paper examines the arguments for such "genetic exceptionalism" and concludes that no clear, significant distinctions between genetic and nongenetic tests justify a different approach to testing by clinicians. Nevertheless, with many genetic tests, the results may cause stigmatization, family discord, and psychological distress. Regardless of whether a test is genetic, when this combination of characteristics is present and when health care providers are not specifically trained to interpret results, testing should be performed with particular caution and the highest standards of informed consent and privacy protection should be applied.
Grimbergen, Y. A. and R. A. Roos (2003). "Therapeutic options for Huntington's disease." Curr Opin Investig Drugs 4(1): 51-4.
Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder. The genetic defect lies in the expansion of a CAG repeat on chromosome 4 and neuropathologically it is characterized by neuronal loss in the striatum. Clinical signs are chorea, impaired voluntary movement, behavioral changes and dementia. Present therapies are limited to these symptoms without any influence on the course of the disease, whereas current pharmacological developments mainly focus on delaying disease progression. This review discusses the present symptomatic treatments and focuses on recent developments of new therapeutic approaches for HD.
Hamilton, J. M., K. Y. Haaland, et al. (2003). "Ideomotor limb apraxia in Huntington's disease: implications for corticostriate involvement." Neuropsychologia 41(5): 614-21.
Ideomotor limb apraxia, a disorder of goal-directed movement, has been attributed to lesions in the frontal and parietal lobes, but the role of subcortical structures is less certain. In order to determine its prevalence in a disorder affecting the basal ganglia and corticostriatal connections, we examined imitation of hand gestures in Huntington's disease (HD) patients. We also assessed the relationship between apraxia and cognitive and motor dysfunction in an effort to better understand the neural underpinnings of apraxia in HD. If damage restricted to the basal ganglia produces ideomotor limb apraxia, then we would expect to find evidence of apraxia in patients who were early in the disease course when selective striatal damage is most common. Such a pattern, however, was not found in our sample. Instead, patients with greater neurological impairment and with a longer duration of disease were more likely than less affected patients to demonstrate apraxia. Apraxia was not related to severity of chorea, but was associated with greater impairment in eye movements, voluntary movements, and verbal fluency. These findings suggest that apraxia in HD results from damage to the corticostriate pathways and the basal ganglia rather than from damage restricted to the basal ganglia.
Hamilton, J. M., D. P. Salmon, et al. (2003). "Behavioural abnormalities contribute to functional decline in Huntington's disease." J Neurol Neurosurg Psychiatry 74(1): 120-2.
The independent and relative contributions of motor, cognitive, and behavioural deficits to functional decline in patients with Huntington's disease are examined. Twenty two patients with Huntington's disease were assessed with rating scales for motor dysfunction, cognitive measures of executive functions, and behavioural measures of apathy, executive dysfunction, and disinhibition. Their functional status was assessed with informant based and clinician based ratings of activities of daily living (ADL). A composite apathy/executive dysfunction behavioural index was strongly related to decline in ADL independently and after controlling for motor and cognitive deficits. These results suggest that behavioural dysfunction contributes to functional decline in patients with Huntington's disease and may impede their ability to utilise motor or cognitive skills that remain available in the early stages of the disease.
Hawkes, C. (2003). "Olfaction in neurodegenerative disorder." Mov Disord 18(4): 364-72.
There has been an increase of interest in olfactory dysfunction since it was realised that anosmia was a common feature of idiopathic Parkinson's disease (PD) and Alzheimer-type dementia (AD). It is an intriguing possibility that the first sign of a disorder hitherto regarded as one of movement or cognition may be that of disturbed smell sense. In this review of PD, parkinsonian syndromes, essential tremor, AD, motor neurone disease (MND) and Huntington's chorea (HC) the following observations are made: 1) olfactory dysfunction is frequent and often severe in PD and AD; 2) normal smell identification in PD is rare and should prompt review of diagnosis unless the patient is female with tremor-dominant disease; 3) anosmia in suspected progressive supranuclear palsy and corticobasal degeneration is atypical and should likewise provoke diagnostic review; 4) hyposmia is an early feature of PD and AD and may precede motor and cognitive signs respectively; 5) subjects with anosmia and one ApoE-4 allele have an approximate 5-fold increased risk of later AD; 6) impaired smell sense is seen in some patients at 50% risk of parkinsonism; 7) smell testing in HC and MND where abnormality may be found, is not likely to be of clinical value; and 8) biopsy of olfactory nasal neurons shows non-specific changes in PD and AD and at present will not aid diagnosis.
Hickey, M. A. and M. F. Chesselet (2003). "Apoptosis in Huntington's disease." Prog Neuropsychopharmacol Biol Psychiatry 27(2): 255-65.
Huntington's disease (HD) is an autosomal dominant, fatal disorder. Patients display increasing motor, psychiatric and cognitive impairment and at autopsy, late-stage patient brains show extensive striatal (caudate and putamen), pallidal and cortical atrophy. The initial and primary target of degeneration in HD is the striatal medium spiny GABAergic neuron, and by end stages of the disease up to 95% of these neurons are lost [J. Neuropathol. Exp. Neurol. 57 (1998) 369]. The disease is caused by an elongation of a polyglutamine tract in the N-terminal of the huntingtin gene, but it is not known how this mutation leads to such extensive, but selective, cell death [Cell 72 (1993) 971]. There is substantial evidence from in vitro studies that connects apoptotic pathways and apoptosis with the mutant protein, and theories linking apoptosis to neuronal death in HD have existed for several years. Despite this, evidence of apoptotic neuronal death in HD is scarce. It may be that the processes involved in apoptosis, rather than apoptosis per se, are more important for HD pathogenesis. Upregulation of the proapoptotic proteins could lead to cleavage of huntingtin and as recent data has shown, the consequent toxic fragment may itself elicit toxic effects on the cell by disrupting transcription. In addition, the increased levels of proapoptotic proteins could contribute to slowly developing cell death in HD, selective for the striatal medium spiny GABAergic neurons and later spreading to other areas. Here we review the evidence supporting these mechanisms of pathogenesis in HD.
Hockly, E., V. M. Richon, et al. (2003). "Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease." Proc Natl Acad Sci U S A 100(4): 2041-6.
Huntington's disease (HD) is an inherited, progressive neurological disorder that is caused by a CAG/polyglutamine repeat expansion and for which there is no effective therapy. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of this disease. Supporting this view, administration of histone deacetylase (HDAC) inhibitors has been shown to rescue lethality and photoreceptor neurodegeneration in a Drosophila model of polyglutamine disease. To further explore the therapeutic potential of HDAC inhibitors, we have conducted preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, in the R6/2 HD mouse model. We show that SAHA crosses the blood-brain barrier and increases histone acetylation in the brain. We found that SAHA could be administered orally in drinking water when complexed with cyclodextrins. SAHA dramatically improved the motor impairment in R6/2 mice, clearly validating the pursuit of this class of compounds as HD therapeutics.
Holbert, S., A. Dedeoglu, et al. (2003). "Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease." Proc Natl Acad Sci U S A 100(5): 2712-7.
Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction. To identify previously uncharacterized htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted SH3 domain protein (K08E3.3b) that interacts with N-terminal htt in two-hybrid tests. A human homolog of K08E3.3b is the Cdc42-interacting protein 4 (CIP4), a protein involved in Cdc42 and Wiskott-Aldrich syndrome protein-dependent signal transduction. CIP4 interacted in vitro with full-length htt from lymphoblastoid cells. Neuronal CIP4 immunoreactivity increased with neuropathological severity in the neostriatum of HD patients and partially colocalized to ubiquitin-positive aggregates. Marked CIP4 overexpression also was observed in Western blot from human HD brain striatum. The overexpression of CIP4 induced the death of striatal neurons. Our data suggest that CIP4 accumulation and cellular toxicity may have a role in HD pathogenesis.
Hsieh, W. Y., Y. L. Hsieh, et al. (2003). "Neural progenitor cells resist excitatory amino acid-induced neurotoxicity." J Neurosci Res 71(2): 272-8.
The applications of neural progenitor cells in clinical therapy for neural degeneration, such as Parkinson's disease, Huntington's disease, and cerebral infarction, have long been explored widely. It had been suggested that these cells may block the apoptosis of ischemia-induced neuronal damage and may themselves resist neurotoxic factors. In the present study, neural progenitor cells derived from the cortex of rodent embryos were cultured with the mitogenic agent epidermal growth factor. It was observed that these progenitor cells could self-renew and differentiate into a number of types of neurons and glial cells. By using sodium nitroprusside, glutamate, and N-methyl-D-aspartate, these neural progenitor cells were shown to have a higher resistance to neurotoxicity induced by these drugs compared with primary neuronal cells. However, the release of nitric oxide in response to glutamate by these neural progenitor cells was similar to the released by primary neuronal cells. Also, when the glutamate-stimulated increase in intracellular free Ca(2+) concentration was measured, stimulation of the glutamate receptors could not induce a significant influx of Ca(2+) into these progenitor cells until they differentiated. Our results suggest that the resistance of neural progenitor cells to neurotoxicity may be partially due to a lack of response to glutamate. In addition, some progenitor-generated neurotrophic factors may contribute to the resistance of these cells to nitric oxide-induced neurotoxicity.
Igarashi, S., H. Morita, et al. (2003). "Inducible PC12 cell model of Huntington's disease shows toxicity and decreased histone acetylation." Neuroreport 14(4): 565-8.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a polyglutamine tract in the huntingtin protein. We have developed PC12 cell lines in which the expression of an N-terminal truncation of huntingtin (N63) with either wild type (23Q) or expanded polyglutamine (148Q) can be induced by the removal of doxycycline. Differentiated PC12 cells induced to express N63-148Q showed cellular toxicity reaching up to 50% at 6 days post-induction. Histone acetyltransferase (HAT) activity and global histone acetylation was significantly decreased in cells expressing truncated huntingtin with mutant but not normal huntingtin. These data suggest that altered chromatin modification via reduction in coactivator activity may cause neuronal transcriptional dysregulation and contribute to cellular toxicity.
Iuchi, S., G. Hoffner, et al. (2003). "Oligomeric and polymeric aggregates formed by proteins containing expanded polyglutamine." Proc Natl Acad Sci U S A 100(5): 2409-14.
Neurological diseases resulting from proteins containing expanded polyglutamine (polyQ) are characteristically associated with insoluble neuronal inclusions, usually intranuclear, and neuronal death. We describe here oligomeric and polymeric aggregates formed in cells by expanded polyQ. These aggregates are not dissociated by concentrated formic acid, an extremely effective solvent for otherwise insoluble proteins. Perinuclear inclusions formed in cultured cells by expanded polyQ can be completely dissolved in concentrated formic acid, but a soluble protein oligomer containing the expanded polyQ and released by the formic acid is not dissociated to monomer. In Huntington's disease, a formic acid-resistant oligomer is present in cerebral cortex, but not in cerebellum. Cortical nuclei contain a polymeric aggregate of expanded polyQ that is insoluble in formic acid, does not enter polyacrylamide gels, but is retained on filters. This finding shows that the process of polymerization is more advanced in the cerebral cortex than in cultured cells. The resistance of oligomer and polymer to formic acid suggests the participation of covalent bonds in their stabilization.
Jellinger, K. A. (2003). "Huntington's Disease (3rd edn)." Eur J Neurol 10(2): 193-4.
Jiang, H., F. C. Nucifora, Jr., et al. (2003). "Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein." Hum Mol Genet 12(1): 1-12.
Huntington's Disease belongs to the CAG repeat family of neurodegenerative diseases and is characterized by the presence of an expanded polyglutamine (polyQ) repeat in the huntingtin (htt) gene product. PolyQ-expanded htt accumulates within large aggregates that are found in various subcellular compartments, but are more often localized within the nucleus. It has been suggested that the sequestration of proteins essential to cell viability may be one mechanism that accounts for toxicity generated by polyQ-expanded proteins. Nuclear inclusions containing polyQ-expanded htt recruit the transcriptional cofactor, CREB-binding protein (CBP). PolyQ toxicity appears to involve alterations of gene transcription and reduced neuronal cell viability. In the HT22 hippocampal cell line, we find that toxicity within individual cells induced by polyQ-expanded htt, as revealed by a TUNEL assay, is associated with the localization of the mutant htt within either nuclear or perinuclear aggregates. However, in addition to CBP recruitment, we show here that CBP ubiquitylation and degradation can be selectively enhanced by polyQ-expanded htt. Thus, selected substrates may be directed to the ubiquitin/proteasome-dependent protein degradation pathway in response to polyQ-expanded htt within the nucleus.
Johnston, M. V., L. Alemi, et al. (2003). "Learning, memory, and transcription factors." Pediatr Res 53(3): 369-74.
Cognitive disorders in children have traditionally been described in terms of clinical phenotypes or syndromes, chromosomal lesions, metabolic disorders, or neuropathology. Relatively little is known about how these disorders affect the chemical reactions involved in learning and memory. Experiments in fruit flies, snails, and mice have revealed some highly conserved pathways that are involved in learning, memory, and synaptic plasticity, which is the primary substrate for memory storage. These can be divided into short-term memory storage through local changes in synapses, and long-term storage mediated by activation of transcription to translate new proteins that modify synaptic function. This review summarizes evidence that disruptions in these pathways are involved in human cognitive disorders, including neurofibromatosis type I, Coffin-Lowry syndrome, Rubinstein-Taybi syndrome, Rett syndrome, tuberous sclerosis-2, Down syndrome, X-linked alpha-thalassemia/mental retardation, cretinism, Huntington disease, and lead poisoning.
Junn, E., R. D. Ronchetti, et al. (2003). "Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies." Proc Natl Acad Sci U S A 100(4): 2047-52.
Proteinaceous aggregates containing alpha-synuclein represent a feature of neurodegenerative disorders such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Despite extensive research, the mechanisms underlying alpha-synuclein aggregation remain elusive. Previously, tissue transglutaminase (tTGase) was found to contribute to the generation of aggregates by cross-linking pathogenic substrate proteins in Huntington's and Alzheimer's diseases. In this article, the role of tTGase in the formation of alpha-synuclein aggregates was investigated. Purified tTGase catalyzed alpha-synuclein cross-linking, leading to the formation of high molecular weight aggregates in vitro, and overexpression of tTGase resulted in the formation of detergent-insoluble alpha-synuclein aggregates in cellular models. Immunocytochemical studies demonstrated the presence of alpha-synuclein-positive cytoplasmic inclusions in 8% of tTGase-expressing cells. The formation of these aggregates was significantly augmented by the calcium ionophore and prevented by the inhibitor cystamine. Immunohistochemical studies on postmortem brain tissue confirmed the presence of transglutaminase-catalyzed varepsilon (gamma-glutamyl)lysine cross-links in the halo of Lewy bodies in Parkinson's disease and dementia with Lewy bodies, colocalizing with alpha-synuclein. These findings, taken together, suggest that tTGase activity leads to alpha-synuclein aggregation to form Lewy bodies and perhaps contributes to neurodegeneration.
Knutson, M. and M. Wessling-Resnick (2003). "Iron metabolism in the reticuloendothelial system." Crit Rev Biochem Mol Biol 38(1): 61-88.
Comprised mainly of monocytes and tissue macrophages, the reticuloendothelial system (RES) plays two major roles in iron metabolism: it recycles iron from senescent red blood cells and it serves as a large storage depot for excess iron. Although iron recycling by the RES represents the largest pathway of iron efflux in the body, the precise mechanisms involved have remained elusive. However, studies characterizing the function and regulation of Nramp1, DMT1, HFE, FPN1, CD163, and hepcidin are rapidly expanding our knowledge of the molecular aspects of RE iron handling. This review summarizes fundamental physiological and biochemical aspects of iron metabolism in the RES and focuses on how recent studies have advanced our understanding of these areas. Also discussed are novel insights into the molecular mechanisms contributing to the abnormal RE iron metabolism characteristic of hereditary hemochromatosis and the anemia of chronic disease.
Lastres-Becker, I., R. de Miguel, et al. (2003). "Compounds acting at the endocannabinoid and/or endovanilloid systems reduce hyperkinesia in a rat model of Huntington's disease." J Neurochem 84(5): 1097-109.
We have recently reported that the administration of AM404, an inhibitor of the endocannabinoid re-uptake process, which also has affinity for the vanilloid VR1 receptors, is able to reduce hyperkinesia, and causes recovery from neurochemical deficits, in a rat model of Huntington's disease (HD) generated by bilateral intrastriatal injections of 3-nitropropionic acid (3NP). In the present study, we wanted to explore the mechanism(s) by which AM404 produces its antihyperkinetic effect in 3NP-lesioned rats by employing several experimental approaches. First, we tried to block the effects of AM404 with selective antagonists for the CB1 or VR1 receptors, i.e. SR141716A and capsazepine, respectively. We found that the reduction caused by AM404 of the increased ambulation exhibited by 3NP-lesioned rats in the open-field test was reversed when the animals had been pre-treated with capsazepine but not with SR141716A, thus suggesting a major role of VR1 receptors in the antihyperkinetic effects of AM404. However, despite the lack of behavioral effects of the CB1 receptor antagonist, the pretreatment with this compound abolished the recovery of neurochemical [gamma-aminobutyric acid (GABA) and dopamine] deficits in the caudate- putamen caused by AM404, as also did capsazepine. In a second group of studies, we wanted to explore the potential antihyperkinetic effects of various compounds which, compared to AM404, exhibit more selectivity for either the endovanilloid or the endocannabinoid systems. First, we tested VDM11 or AM374, two selective inhibitors or the endocannabinoid re-uptake or hydrolysis, respectively. Both compounds were mostly unable to reduce hyperkinesia in 3NP-lesioned rats, although VDM11 produced a certain motor depression, and AM374 exhibited a trend to stimulate ambulation, in control rats. We also tested the effects of selective direct agonists for VR1 (capsaicin) or CB1 (CP55,940) receptors. Capsaicin exhibited a strong antihyperkinetic activity and, moreover, was able to attenuate the reductions in dopamine and GABA transmission provoked by the 3NP lesion, whereas CP55,940 had also antihyperkinetic activity but was unable to cause recovery of either dopamine or GABA deficits in the basal ganglia. In summary, our data indicate a major role for VR1 receptors, as compared to CB1 receptors, in the antihyperkinetic effects and the recovery of neurochemical deficits caused in 3NP-lesioned rats by compounds that activate both CB1 and VR1 receptors, either directly or via manipulation of the levels of endogenous agonists.
Lee, J. A., C. S. Lim, et al. (2003). "Aggregate formation and the impairment of long-term synaptic facilitation by ectopic expression of mutant huntingtin in Aplysia neurons." J Neurochem 85(1): 160-169.
Huntington's disease (HD) is caused by an expansion of a polyglutamine (polyQ) tract within huntingtin (htt) protein. To examine the cytotoxic effects of polyQ-expanded htt, we overexpressed an enhanced green fluorescent protein (EGFP)-tagged N-terminal fragment of htt with 150 glutamine residues (Nhtt150Q-EGFP) in Aplysia neurons. A combined confocal and electron microscopic study showed that Aplysia neurons expressing Nhtt150Q-EGFP displayed numerous abnormal aggregates (diameter 0.5-5 micro m) of filamentous structures, which were formed rapidly (approximately 2 h) but which were sustained for at least 18 days in the cytoplasm. Furthermore, the overexpression of Nhtt150Q-EGFP in sensory cells impaired 5-hydroxytryptamine (5-HT)-induced long-term synaptic facilitation in sensori-motor synapses without affecting basal synaptic strength or short-term facilitation. This study demonstrates the stability of polyQ-based aggregates and their specific effects on long-term synaptic plasticity.
Leng, T. R., M. J. Woodward, et al. (2003). "Effects of multisensory stimulation in people with Huntington's disease: a randomized controlled pilot study." Clin Rehabil 17(1): 30-41.
OBJECTIVE: To investigate whether behavioural, motor and physiological responses of individuals with Huntington's disease (HD) to a controlled multisensory environment (MSE) are effective as a therapeutic (sustained effects) or leisure (immediate effects) activity. DESIGN: Pilot study--a randomized, controlled, two-group design. SETTING: Specialist residential unit for people with mid-late stage HD. SUBJECTS: Twelve patients with HD (one subject from each group dropped out during the study after week 8 due to medical complications). INTERVENTIONS: Patients attended eight, 30-minute sessions over a four-week period, of multisensory stimulation (MSE, treatment group) or relaxation activities (control group). MAIN OUTCOME MEASURES: Between-group comparisons for changes between assessment sessions for two behavioural assessments: Rehabilitation Evaluation--Hall and Baker (REHAB), Behaviour and Mood Disturbance Scale (BMD); a motor assessment: the dyskinesia section of the St Hans Rating Scale (SHRS); physiological measures: blood pressure, heart rate and respiratory rate. Secondary measures during intervention sessions included behavioural assessment using the Interact. RESULTS: There were no significant differences found between the groups for any main outcome measures made between sessions. The MSE group showed some positive effects within-sessions, with the Interact showing significant between-group differences in immediate effects on mood (p = 0.028). There was also a significantly different change over time for within-session changes in stimulation levels (p = 0.0002) and mood (p = 0.0001) between the groups. No physiological effects were observed in relation to sessions in either group. Two MSE subjects underwent changes in medication during the study period. CONCLUSIONS: There was no therapeutic effect of MSEs over the four-week study period. MSEs appear to be more effective thanconventional relaxation techniques as a leisure activity.
Lesort, M., M. Lee, et al. (2003). "Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders." J Biol Chem 278(6): 3825-30.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormally expended polyglutamine domain. There is no effective treatment for HD; however, inhibition of caspase activity or prevention of mitochondria dysfunction delays disease progression in HD mouse models. Similarly administration of cystamine, which can inhibit transglutaminase, prolonged survival of HD mice, suggesting that inhibition of transglutaminase might provide a new treatment strategy. However, it has been suggested that cystamine may inhibit other thiol-dependent enzymes in addition to transglutaminase. In this study we show that cystamine inhibits recombinant active caspase-3 in a concentration-dependent manner. At low concentrations cystamine is an uncompetitive inhibitor of caspase-3 activity, becoming a non-competitive inhibitor at higher concentrations. The IC(50) for cystamine-mediated inhibition of caspase-3 activity in vitro was 23.6 microm. In situ cystamine inhibited in a concentration-dependent manner the activation of caspase-3 by different pro-apoptotic agents. Additionally, cystamine inhibited caspase-3 activity to the same extent in cell lines stably overexpressing wild type tissue transglutaminase (tTG), a mutant inactive tTG, or an antisense for tTG, demonstrating that cystamine inhibits caspase activity independently of any effects it may have on the transamidating activity of tTG. Finally, treatment with cystamine resulted in a robust increase in the levels of glutathione. These findings demonstrate that cystamine may prolong neuronal survival and delay the onset of HD by inhibiting caspases and increasing the level of antioxidants such as glutathione.
Li, S. H. and X. J. Li (2003). "In vitro expression systems for the Huntington protein." Methods Mol Biol 217: 277-84.
Lorenzl, S., D. S. Albers, et al. (2003). "Tissue inhibitors of matrix metalloproteinases are elevated in cerebrospinal fluid of neurodegenerative diseases." J Neurol Sci 207(1-2): 71-6.
Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases such as Alzheimer's Disease (AD) and amyotrophic lateral sclerosis (ALS). Increased expression of MMP-9 and TIMPs has been reported in postmortem AD and ALS brain tissue, as well as in ALS cerebrospinal fluid (CSF) and plasma. Although individual studies of MMP and TIMP expression in CSF have included AD and ALS samples, there are no studies comparing the expression of these proteins between neurodegenerative diseases. We measured the levels of matrix metalloproteinases (MMPs)-2 and -9 and the tissue inhibitor of MMPs (e.g. TIMP-1 and TIMP-2) in CSF samples from patients with Parkinson's Disease (PD), Huntington's Disease (HD), AD and ALS as compared to age-matched control patients. There was constitutive expression of the proform of gelatinase A (proMMP-2) on zymography gels in all CSF samples. Unexpectedly, there was an additional gelatinolytic band at 130 kDa of unknown etiology in the CSF samples of patients with PD (61% of patients studied), AD (61%), HD (25%) and ALS (39%). Levels of TIMP-1 were significantly elevated in CSF samples from all disease groups. TIMP-2 was significantly increased in CSF of AD and HD patients. MMP-2 levels did not differ significantly between groups. These findings show that TIMPs are elevated in the CSF of patients with neurodegenerative diseases suggesting a potential role of these endogenous inhibitors of matrix metalloproteinases in neurodegenerative diseases.
Mattson, M. P., W. Duan, et al. (2003). "Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms." J Neurochem 84(3): 417-31.
Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.
McMurray, C. T. and I. V. Kortun (2003). "Repair in haploid male germ cells occurs late in differentiation as chromatin is condensing." Chromosoma.
Huntington's Disease (HD) is one of eight progressive neurodegenerative disorders in which the underlying mutation is a CAG expansion encoding a polyglutamine tract. The mechanism of trinucleotide expansion remains poorly understood. We have followed heritable changes in CAG length in male transgenic mice. In germ cells, expansion is limited to the post-meiotic, haploid cell and therefore cannot involve mitotic replication or recombination between a homologous chromosome and a sister chromatid. Expansion occurs by gap filling synthesis when DNA loops comprising the CAG trinucleotide repeats are sealed into the DNA strand. Our data support a model in which expansion occurs late in male germ cell development as spermatids are entering the epididymis at a time when chromatin is condensing. These data indicate that repair can be carried out in germ cells as long as the DNA is accessible. The capacity for repair of germ cells may have important implications for future gene therapy.
Norremolle, A., M. Grunnet, et al. (2003). "Cells exposed to a huntingtin fragment containing an expanded polyglutamine tract show no sign of ion channel formation: results arguing against the ion channel hypothesis." J Neurosci Res 71(1): 132-7.
Ion channels formed by expanded polyglutamine tracts have been proposed to play an important role in the pathological processes leading to neurodegeneration in Huntington's disease and other CAG repeat diseases. We tested the capacity of a huntingtin fragment containing an expanded polyglutamine tract to form ion channels in two cell types. Whole cell current from Xenopus oocytes was recorded using two-electrode voltage-clamp technique, and whole cell current from CHO-K1 cells was recorded by patch-clamp technique. The fragment with an expanded polyglutamine sequence induced no change in the currents recorded in any of the two expression systems, indicating no changes in ion channel activity. The results therefore argue against the proposed hypothesis of expanded polyglutamines forming ion channels.
Nucifora, F. C., Jr., L. M. Ellerby, et al. (2003). "Nuclear Localization of a Non-caspase Truncation Product of Atrophin-1, with an Expanded Polyglutamine Repeat, Increases Cellular Toxicity." J Biol Chem 278(15): 13047-13055.
Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder similar to Huntington's disease, with clinical manifestations including chorea, incoordination, ataxia, and dementia. It is caused by an expansion of a CAG trinucleotide repeat encoding polyglutamine in the atrophin-1 gene. Both patients and DRPLA transgenic mice have nuclear accumulation of atrophin-1, especially an approximately 120-kDa fragment, which appears to represent a cleavage product. We now show that this is an N-terminal fragment that does not correspond to the previously described caspase-3 fragment, or any other known caspase cleavage product. The atrophin-1 sequence contains a putative nuclear localization signal in the N terminus of the protein and a putative nuclear export signal in the C terminus. We have tested the hypothesis that endogenous localization signals are functional in atrophin-1, and that nuclear localization and proteolytic cleavage contribute to atrophin-1 cell toxicity. In transient cell transfection experiments using a neuroblastoma cell line, full-length atrophin-1 with 26 (normal) or 65 (expanded) glutamines localized to both nucleus and cytoplasm, with no significant difference in toxicity between the normal and mutant proteins. A construct with 65 glutamine repeats encoding an N-terminal fragment (which removes an NES) of atrophin-1 similar in size to the truncation product in DRPLA patient tissue, showed increased nuclear labeling, and an increase in cellular toxicity, compared with a similar fragment with 26 glutamines. Full-length atrophin-1 with 65 polyglutamine repeats and mutations inactivating the NES also yielded increased nuclear localization and increased toxicity. These data suggest that truncation enhances cellular toxicity of the mutant protein, and that the NES is a relevant region deleted during truncation. Furthermore, mutating the NLS in the truncated protein shifted atrophin-1 more to the cytoplasm and eliminated the increased toxicity, consistent with the idea that nuclear localization enhances toxicity. In none of the experiments were inclusions visible in the nucleus or cytoplasm suggesting that inclusion formation is unrelated to cell death. These data indicate that truncation of atrophin-1 may alter its ability to shuttle between the nucleus and cytoplasm, leading to abnormal nuclear interactions and cell toxicity.
Okano, A., N. Usuda, et al. (2003). "Huntingtin-interacting protein-1-related protein of rat (rHIP1R) is localized in the postsynaptic regions." Brain Res 967(1-2): 210-25.
We cloned a rHIP1R (GenBank Accession No., AB005052) encoding a Sla2/huntingtin-interacting protein (HIP1) family protein from a rat brain cDNA library. Localization of rHIP1R was investigated in the rat brain using an antibody specific to the HIP1R antibody. The rHIP1R protein was enriched in the synaptic plasma membrane fraction along with huntingtin, a synaptic protein and a causal protein for Huntington's disease. The electron microscopic examination revealed that HIP1R was localized at postsynaptic spines. Localization of HIP1R in the small vesicular structures in the spine, possible sites of vesicular transport of synaptic proteins, together with the structure-based analysis, suggested a role of HIP1R for vesicle trafficking through interaction with F-actin and working together with huntingtin and HIP1 at the synaptic sites.
Orcutt, C. J. (2003). "Ferret urogenital diseases." Veterinary Clin North Am Exot Anim Pract 6(1): 113-38.
Improved nutrition and client education have decreased the incidence of certain urinary tract diseases in ferrets. Early neutering programs at commercial breeding farms in the United States have also led to a marked decrease in the incidence of reproductive tract disease, especially estrogen-induced bone marrow suppression. However, the increased incidence of adrenal disease and its secondary effects on reproductive and associated urinary tract tissue presents an ongoing challenge for the clinician working with pet ferrets. Acute and chronic renal failure remain important, though less common, disease entities. It is imperative that the veterinarian working with pet ferrets be aware of the clinical presentation and clinicopathologic abnormalities associated with these syndromes.
Ostenfeld, T. and C. N. Svendsen (2003). "Recent advances in stem cell neurobiology." Adv Tech Stand Neurosurg 28: 3-89.
1. Neural stem cells can be cultured from the CNS of different mammalian species at many stages of development. They have an extensive capacity for self-renewal and will proliferate ex vivo in response to mitogenic growth factors or following genetic modification with immortalising oncogenes. Neural stem cells are multipotent since their differentiating progeny will give rise to the principal cellular phenotypes comprising the mature CNS: neurons, astrocytes and oligodendrocytes. 2. Neural stem cells can also be derived from more primitive embryonic stem (ES) cells cultured from the blastocyst. ES cells are considered to be pluripotent since they can give rise to the full cellular spectrum and will, therefore, contribute to all three of the embryonic germ layers: endoderm, mesoderm and ectoderm. However, pluripotent cells have also been derived from germ cells and teratocarcinomas (embryonal carcinomas) and their progeny may also give rise to the multiple cellular phenotypes contributing to the CNS. In a recent development, ES cells have also been isolated and grown from human blastocysts, thus raising the possibility of growing autologous stem cells when combined with nuclear transfer technology. 3. There is now an emerging recognition that the adult mammalian brain, including that of primates and humans, harbours stem cell populations suggesting the existence of a previously unrecognised neural plasticity to the mature CNS, and thereby raising the possibility of promoting endogenous neural reconstruction. 4. Such reports have fuelled expectations for the clinical exploitation of neural stem cells in cell replacement or recruitment strategies for the treatment of a variety of human neurological conditions including Parkinson's disease (PD), Huntington's disease, multiple sclerosis and ischaemic brain injury. Owing to their migratory capacity within the CNS, neural stem cells may also find potential clinical application as cellular vectors for widespread gene delivery and the expression of therapeutic proteins. In this regard, they may be eminently suitable for the correction of genetically-determined CNS disorders and in the management of certain tumors responsive to cytokines. Since large numbers of stem cells can be generated efficiently in culture, they may obviate some of the technical and ethical limitations associated with the use of fresh (primary) embryonic neural tissue in current transplantation strategies. 5. While considerable recent progress has been made in terms of developing new techniques allowing for the long-term culture of human stem cells, the successful clinical application of these cells is presently limited by our understanding of both (i) the intrinsic and extrinsic regulators of stem cell proliferation and (ii) those factors controlling cell lineage determination and differentiation. Although such cells may also provide accessible model systems for studying neural development, progress in the field has been further limited by the lack of suitable markers needed for the identification and selection of cells within proliferating heterogeneous populations of precursor cells. There is a further need to distinguish between the committed fate (defined during normal development) and the potential specification (implying flexibility of fate through manipulation of its environment) of stem cells undergoing differentiation. 6. With these challenges lying ahead, it is the opinion of the authors that stem-cell therapy is likely to remain within the experimental arena for the foreseeable future. In this regard, few (if any) of the in vivo studies employing neural stem cell grafts have shown convincingly that behavioural recovery can be achieved in the various model paradigms. Moreover, issues relating to the quality control of cultured cells and their safety following transplantation have only begun to be addressed. 7. While on the one hand cell biotechnologists have been quick to realise the potential commercial value, human stem cell research and its clinical applications has been the subject of intense ethical and legislative considerations. The present chapter aims to review some recent aspects of stem cell research applicable to developmental neurobiology and the potential applications in clinical neuroscience.
Panov, A. V., J. R. Burke, et al. (2003). "In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington's disease." Arch Biochem Biophys 410(1): 1-6.
The mechanisms by which neurons die in CAG triplet repeat (polyglutamine) disorders, such as Huntington's disease, are uncertain; however, mitochondrial dysfunction and disordered calcium homeostasis have been implicated. We previously demonstrated abnormal mitochondrial calcium handling in Huntington's disease cell lines and transgenic mice. To examine whether these abnormalities might arise in part from direct effects of the expanded polyglutamine tract contained in mutant huntingtin, we have exposed normal rat liver and human lymphoblast mitochondria to glutathione S-transferase fusion proteins containing polyglutamine tracts of 0, 19, or 62 residues. Similar to bovine serum albumin, each of the protein constructs nonspecifically inhibited succinate-supported respiration, independent of polyglutamine tract length. There was a small but significant reduction of mitochondrial membrane potential (state 4) only in the presence of the pathological-length polyglutamine tract. With successive addition of small Ca(2+) aliquots, mitochondria exposed to pathological-length polyglutamine tracts (approximately 5 microM) depolarized much earlier and to a greater extent than those exposed to the other protein constructs. These results suggest that the mitochondrial calcium handling defects seen in Huntington's disease cell lines and transgenic mice may be due, in part, to direct, deleterious effects of mutant huntingtin on mitochondria.
Pavese, N., T. C. Andrews, et al. (2003). "Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study." Brain 126(Pt 5): 1127-35.
We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.
Pei, J. J., S. Khatoon, et al. (2003). "Role of protein kinase B in Alzheimer's neurofibrillary pathology." Acta Neuropathol (Berl) 105(4): 381-92.
Protein kinase B (PKB) is an important intermediate in the phosphatidylinositol-3 kinase signaling cascade that acts to phosphorylate glycogen synthase kinase-3 (GSK-3) at its serine 9 residue, thereby inactivating it. Activated GSK-3 has been previously shown to be preferentially associated with neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. In the present study, we performed immunohistochemistry with an antibody to the active form of PKB in brains with different stages of neurofibrillary degeneration. We found that the amount of activated PKB (p-Thr308) increased in correlation to the progressive sequence of AT8 immunoreactivity and neurofibrillary changes assessed according to Braak's criteria. By confocal microscopy, activated PKB (p-Thr308) was found to appear in particular in neurons that are known to later develop NFTs in AD. Western blotting showed that activated PKB was increased by more than 50% in the 16,000- g supernatants of AD brains as compared with normal aged and Huntington's disease controls. This increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site. These studies suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.
Rashid, M. N., F. Fuentes, et al. (2003). "Obesity and the risk for cardiovascular disease." Prev Cardiol 6(1): 42-7.
Coronary heart disease (CHD) is the leading cause of mortality in the United States. Hypertension, diabetes mellitus, hypercholesterolemia, and smoking have all been directly related to CHD. Obesity is on the rise in the United States and has also been associated with CHD. This review clearly establishes obesity as an independent risk factor for CHD as demonstrated by the Framingham Heart Study, Nurses Health Study, Buffalo Health Study, and the Cancer Prevention Study II. Morbid obesity was found to correlate with a significant risk of mortality from CHD, especially in young men. Prevention of obesity, and therefore reduction in risk from cardiovascular disease, is paramount in the management of obesity. New approaches to behavioral, medical, and surgical management of obesity are reviewed, including thalidomide, an antiangiogenic agent. A primary and secondary prevention model details a multidisciplinary approach to reducing risk in obesity. Copyright 2003 CHF, Inc.
Romagnoli, A., S. Oliverio, et al. (2003). "Neuroleukin inhibition sensitises neuronal cells to caspase-dependent apoptosis." Biochem Biophys Res Commun 302(3): 448-53.
Neuroleukin (NLK) is a multifunctional protein, involved in neuronal growth, glucose metabolism, cell motility, and differentiation. Expressed in the brain, it supports the growth of embryonic spinal, skeletal motor, and sensory neurons. We have previously demonstrated that NLK is up-regulated in the brain during Huntington's disease (HD), a neurodegenerative disorder caused by the expansion of CAG trinucleotide repeats. In order to study the biological role of NLK, we have generated an inducible rat pheochromocytoma PC12 cell line in which the expression of NLK is selectively down-regulated by antisense strategy. We show here that the block of NLK commits PC12 cells to caspase-dependent apoptosis. This priming effect elicited by NLK inhibition is independent from the differentiation state of the neuronal cells. These results suggest a general protective role of NLK in the control of cell death in neuronal cells.
Sanchez, I., C. Mahlke, et al. (2003). "Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders." Nature 421(6921): 373-9.
The expansion of a CAG repeat coding for polyglutamine in otherwise unrelated gene products is central to eight neurodegenerative disorders including Huntington's disease. It has been well documented that expanded polyglutamine fragments, cleaved from their respective full-length proteins, form microscopically visible aggregates in affected individuals and in transgenic mice. The contribution of polyglutamine oligomers to neurodegeneration, however, is controversial. The azo-dye Congo red binds preferentially to beta-sheets containing amyloid fibrils and can specifically inhibit oligomerization and disrupt preformed oligomers. Here we show that inhibition of polyglutamine oligomerization by Congo red prevents ATP depletion and caspase activation, preserves normal cellular protein synthesis and degradation functions, and promotes the clearance of expanded polyglutamine repeats in vivo and in vitro. Infusion of Congo red into a transgenic mouse model of Huntington's disease, well after the onset of symptoms, promotes the clearance of expanded repeats in vivo and exerts marked protective effects on survival, weight loss and motor function. We conclude that oligomerization is a crucial determinant in the biochemical properties of expanded polyglutamine that are central to their chronic cytotoxicity.
Savitz, S. L., S. Malhotra, et al. (2003). "Cell transplants offer promise for stroke recovery." J Cardiovasc Nurs 18(1): 57-61.
Cell transplantation is an experimental approach to restore brain function in neurodegenerative disorders such as Parkinson's and Huntington's disease. Transplantation also represents a possible strategy to repair the brain after a stroke. Various cell types are under investigation in experimental stroke studies. This review discusses the different graft sources and presents preliminary data on the transplantation of neural progenitor cells after stroke in rats. Following transplantation, progenitor cells proliferated and differentiated into all the different brain cell types, including neurons, and they repopulated the ischemic infarct. These results suggest that cell transplantation may serve as a future restorative therapy for stroke and other neurologic disorders such as Parkinson's disease, Alzheimer's disease, trauma, and multiple sclerosis.
Seiss, E., P. Praamstra, et al. (2003). "Proprioceptive sensory function in Parkinson's disease and Huntington's disease: evidence from proprioception-related EEG potentials." Exp Brain Res 148(3): 308-19.
In both Parkinson's disease and Huntington's disease, proprioceptive sensory deficits have been suggested to contribute to the motor manifestations of the disease. Here, proprioceptive sensory function was investigated in Parkinson's disease patients, Huntington's disease patients, and healthy control subjects (each group n=8), using proprioception-related evoked potentials. Proprioception-related potentials were elicited by passive index finger movements and measured with high-density EEG. Conventional median nerve somatosensory evoked potentials (mnSEPs) were recorded in the same session. Analysis included amplitude and latency measures from selected scalp electrodes and dipole source reconstruction. We found a proprioception-related N90 component of normal latency in both Parkinson's disease and Huntington's disease. The source strength of the underlying cortical generator was normal in Parkinson's disease, but marginally reduced in Huntington's disease. Using the source location of the N20-P20 component of the mnSEP as a landmark for postcentral area 3b, the N90 was localized to the precentral motor cortex. At a latency around 170-180 ms proprioception-related potentials were explained by bilateral sensory cortex activation with an altered distribution in Parkinson's disease and a reduction of ipsilateral activation in Huntington's disease. Together, the results show largely normal early proprioception-related potentials, but changes in the cortical processing of kinaesthetic signals at longer latencies in both diseases.
Sharp, A. and J. Hurst (2003). "Somatic instability of the androgen receptor CAG repeat in a normal female." Am J Med Genet 117A(2): 161-3.
The polyglutamine repeat disorders represent a family of degenerative neurological diseases which are characterized by expansions of tandemly repeated CAG repeats. Investigations have demonstrated that in Huntington disease, dentatorubral pallidoluysian atrophy, and the spinocerebellar ataxias type 1, 2, and 3, the polyglutamine expansions show both meiotic and mitotic instability. However, previous studies have suggested that the polyglutamine motif within exon 1 of the androgen receptor gene (AR) which expands in cases of spinobulbar muscular atrophy differs in that it is apparently mitotically stable. During linkage analysis in a family with FG syndrome, a rare condition mapped to Xq12-q22.1, we detected the presence of an unusually small AR allele segregating within the pedigree. Sequencing, cytogenetic analysis, and PCR of flanking markers indicate that this allele arose by a somatic contraction of seven CAG repeats in the proband's mother, representing the first report of mitotic instability of an AR CAG repeat of normal size.
Silver, A. (2003). "Cognitive-behavioural therapy with a Huntington's gene positive patient." Patient Educ Couns 49(2): 133-8.
The treatment of choice for depression or anxiety after genetic testing is the use of medication. The present paper reports a case of a lady who had a positive test result for Huntington's disease (HD). After the predictive test her mood declined and she experienced symptoms of anxiety. Cognitive-behavioural therapy (CBT) enabled her to deal effectively with her negative automatic thoughts (NATs) and interpret situations more realistically. Therapy was successful in reducing her level of physical, behavioural and affective symptoms and in increasing her sense of control. These gains were maintained at 3 and 6 months in spite of the death of her mother. The paper discussed the potential value of cognitive-behavioural theory and therapy in similar cases.
Snowden, J. S., Z. C. Gibbons, et al. (2003). "Social cognition in frontotemporal dementia and Huntington's disease." Neuropsychologia 41(6): 688-701.
Frontotemporal dementia (FTD) and Huntington's disease (HD) are degenerative disorders, with predominant involvement, respectively of frontal neocortex and striatum. Both conditions give rise to altered social conduct and breakdown in interpersonal relationships, although the factors underlying these changes remain poorly defined. The study used tests of theory of mind (interpretation of cartoons and stories and judgement of preference based on eye gaze) to explore the ability of patients with FTD and HD to interpret social situations and ascribe mental states to others. Performance in the FTD group was severely impaired on all tasks, regardless of whether the test condition required attribution of a mental state. The HD group showed a milder impairment in cartoon and story interpretation, and normal preference judgements. Qualitative differences in performance were demonstrated between groups. FTD patients made more concrete, literal interpretations, whereas HD patients were more likely to misconstrue situations. The findings are interpreted as demonstrating impaired theory of mind in FTD, as one component of widespread executive deficits. In HD the evidence does not suggest a fundamental loss of theory of mind, but rather a tendency to draw faulty inferences from social situations. It is concluded that social breakdown in FTD and HD may have a different underlying basis and that the frontal neocortex and striatum have distinct contributions to social behaviour.
Squitieri, F., C. Gellera, et al. (2003). "Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course." Brain 126(Pt 4): 946-55.
Huntington disease is caused by a dominantly transmitted CAG repeat expansion mutation that is believed to confer a toxic gain of function on the mutant protein. Huntington disease patients with two mutant alleles are very rare. In other poly(CAG) diseases such as the dominant ataxias, inheritance of two mutant alleles causes a phenotype more severe than in heterozygotes. In this multicentre study, we sought differences in the disease features between eight homozygotes and 75 heterozygotes for the Huntington disease mutation. We identified subjects homozygous for the Huntington disease mutation by DNA testing and compared their clinical features (age at onset, symptom presentation, disease severity and disease progression) with those of a group of heterozygotes, who were assessed longitudinally. The age at onset of symptoms in the homozygote cases was within the range expected for heterozygotes with the same CAG repeat lengths, whereas homozygotes had a more severe clinical course. The observation of a more rapid decline in motor, cognitive and behavioural symptoms in homozygotes was consistent with the extent of neurodegeneration as available at imaging in three patients, and at the post-mortem neuropathological report in one case. Our analysis suggests that although homozygosity for the Huntington disease mutation does not lower the age at onset of symptoms, it affects the phenotype and the rate of disease progression. These data, once confirmed in a larger series of patients, point to the possibility that the mechanisms underlying age at onset and disease progression in Huntington disease may differ.
Steffan, J. S. and L. M. Thompson (2003). "Targeting aggregation in the development of therapeutics for the treatment of Huntington's disease and other polyglutamine repeat diseases." Expert Opin Ther Targets 7(2): 201-13.
Huntington's disease (HD) is one of a number of familial polyglutamine (polyQ) repeat diseases. These neurodegenerative disorders are caused by expression of otherwise unrelated proteins that contain an expansion of a polyQ tract, rendering them toxic to specific subsets of vulnerable neurons. These expanded repeats have an inherent propensity to aggregate; insoluble neuronal nuclear and cytoplasmic polyQ aggregates or inclusions are hallmarks of the disorders [1,2]. In HD, inclusions in diseased brains often precede onset of symptoms, and have been proposed to be involved in pathogenicity [3-5]. Various strategies to block the process of aggregation have been developed in an effort to create drugs that decrease neurotoxicity. A discussion of the effect of antibodies, caspase inhibitors, chemical inhibitors, heat-shock proteins, suppressor peptides and transglutaminase inhibitors upon aggregation and disease is presented.
Su, Z. Z., M. Leszczyniecka, et al. (2003). "Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2)." Proc Natl Acad Sci U S A 100(4): 1955-60.
Glutamate transport is central to neurotransmitter functions in the brain. Impaired glutamate transport induces neurotoxicity associated with numerous pathological processes, including stroke/ischemia, temporal lobe epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-1-associated dementia, and growth of malignant gliomas. Excitatory amino acid transporter-2 (EAAT2) is a major glutamate transporter in the brain expressed primarily in astrocytes. We presently describe the cloning and characterization of the human EAAT2 promoter, demonstrating elevated expression in astrocytes. Regulators of EAAT2 transport, both positive and negative, alter EAAT2 transcription, promoter activity, mRNA, and protein. These findings imply that transcriptional processes can regulate EAAT2 expression. Moreover, they raise the intriguing possibility that the EAAT2 promoter may be useful for targeting gene expression in the brain and for identifying molecules capable of modulating glutamate transport that could potentially inhibit, ameliorate, or prevent various neurodegenerative diseases.
Tassicker, R., J. Savulescu, et al. (2003). "Prenatal diagnosis requests for Huntington's disease when the father is at risk and does not want to know his genetic status: clinical, legal, and ethical viewpoints." Bmj 326(7384): 331-3.
Temussi, P. A., L. Masino, et al. (2003). "From Alzheimer to Huntington: why is a structural understanding so difficult?" Embo J 22(3): 355-61.
An increasing family of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, prion encephalopathies and cystic fibrosis is associated with aggregation of misfolded polypeptide chains which are toxic to the cell. Knowledge of the three-dimensional structure of the proteins implicated is essential for understanding why and how endogenous proteins may adopt a non-native fold. Yet, structural work has been hampered by the difficulty of handling proteins insoluble or prone to aggregation, and at the same time that is why it is interesting to study these molecules. In this review, we compare the structural knowledge accumulated for two paradigmatic misfolding disorders, Alzheimer's disease (AD) and the family of poly-glutamine diseases (poly-Q) and discuss some of the hypotheses suggested for explaining aggregate formation. While a common mechanism between these pathologies remains to be proven, a direct comparison may help in designing new strategies for approaching their study.
Thomas, M., W. D. Le, et al. (2003). "Minocycline and other tetracycline derivatives: a neuroprotective strategy in Parkinson's disease and Huntington's disease." Clin Neuropharmacol 26(1): 18-23.
Timman, R., A. Maat-Kievit, et al. (2003). "Testing the test-why pursue a better test for Huntington disease?" Am J Med Genet 117B(1): 79-85.
In 1993, the gene mutation for Huntington disease (HD) was identified and testing became possible with a reliability of >99%, without the need for co-operation of relatives. In 1997, a systematic information program offered the mutation retest to individuals who had earlier received a linkage test result for HD, which has a residual uncertainty of 1-9%. The characteristics of 129 individuals tested by linkage analysis for HD are reported on, as well as the reasons for their reassessment by mutation testing. Three groups were compared: (1) people who were retested between 1993 and 1997, before this study had started, (2) people who were retested after we provided information, and (3) persons who refrained from retesting. Nearly half of the linkage-tested individuals were retested, with the exception of noncarriers with a residual risk of 1 or 2%. Of them, less than one out of five were retested. Carriers with a hopeful view on the future (BHS) and a better sense of well-being (GHQ) were more likely to have the retest. Female carriers were also more likely to have the retest before we contacted them. Noncarriers who were retested were more anxious (HADS) than noncarriers who refrained from the retest. Retestees were younger at the time of testing. No risk reversals were revealed by this study.
van Vugt, J. P., M. Stijl, et al. (2003). "Impaired antagonist inhibition may contribute to akinesia and bradykinesia in Huntington's disease." Clin Neurophysiol 114(2): 295-305.
OBJECTIVE: To test the hypothesis that besides impaired agonist facilitation, impaired antagonist inhibition also contributes to delayed initiation (akinesia) and slow execution (bradykinesia) of voluntary movements in Huntington's disease. METHODS: Fifteen patients with Huntington's disease and 11 age-matched controls participated in the study. The amount of agonist facilitation was measured as the increase in soleus H-reflex amplitude prior to ballistic voluntary plantar flexion (soleus contraction). Antagonist inhibition was measured as the decrease in soleus H-reflex prior to ballistic dorsiflexion (tibialis anterior (TA) contraction). The amount of agonist facilitation and antagonist inhibition was correlated with the time needed for motor initiation (reaction time) and movement execution (movement time). RESULTS: Starting 50ms prior to soleus contraction, soleus H-reflex increased in control subjects but less so in patients. Soleus H-reflexes decreased in controls 25ms prior to TA contraction, while this antagonist inhibition was completely lacking in patients. Thus, patients with Huntington's disease not only displayed reduced agonist facilitation, but impaired antagonist inhibition as well. Moreover, more impairment of antagonist inhibition correlated significantly with more severe akinesia and bradykinesia. CONCLUSIONS: Antagonist inhibition prior to and during agonist contractions is markedly impaired in Huntington's disease. This impairment might contribute to motor slowness in these patients.
Vnencak-Jones, C. L. (2003). "Fluorescence PCR and GeneScan analysis for the detection of CAG repeat expansions associated with Huntington's disease." Methods Mol Biol 217: 101-8.
von Horsten, S., I. Schmitt, et al. (2003). "Transgenic rat model of Huntington's disease." Hum Mol Genet 12(6): 617-24.
Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.
Wang, K., R. Hoosain, et al. (2003). "Impairment of recognition of disgust in Chinese with Huntington's or Wilson's disease." Neuropsychologia 41(5): 527-37.
The selective involvement of the basal ganglia in recognition of the facial expression of disgust was investigated by examining a group of six symptomatic Huntington's disease patients and 32 Wilson's disease patients in China. Morphed photographs of facial expressions covering happiness-surprise-fear-sadness-disgust-anger were used and the patients were asked to label each photo. Other measures assessed basic cognitive functions and perception of non-emotion facial information, such as perception of gender, age, gaze direction, and recognition of unfamiliar as well as famous people. There was dissociation between the perception of emotions and other facial information, and between impairment of recognition of disgust and other emotions. The basal ganglia are the overlapping substrate involved in both Huntington's and Wilson's disease, although each has its own other lesions. The differentially severe impairment of recognition of disgust in the Chinese Huntington's disease and Wilson's disease patients strengthens the view that basal ganglia are selectively involved in processing the emotion of disgust.
Weimer, E., S. Ries, et al. (2003). "[Frontal Dysfunctions in Huntington's Disease]." Psychiatr Prax 30(1): 33-6.
Huntington's disease is a hereditary and progressive disease of the central nervous system. Sudden and irregular hyperkinesias are prominent. Psychopathological findings are very frequent and often proceed the decline of motor functions for years. Almost all the patients develop a dementia in later stages of the illness. This case study shows the treatment of a patient with Huntington's disease, verified by genetic analysis, with the atypical antipsychotic drug amisulpride. In this case the psychiatric disturbances and cognitive impairments were the only signs of the disease. The treatment showed an impressive improvement. Neuropsychological aspects of the disease are discussed.
Weinelt, S., S. Peters, et al. (2003). "Ciliary neurotrophic factor overexpression in neural progenitor cells (ST14A) increases proliferation, metabolic activity, and resistance to stress during differentiation." J Neurosci Res 71(2): 228-36.
Neurotrophic factors exert considerable neuroprotective and neurorestorative effects in neurodegenerative diseases. Because neuronal progenitor cells have, at least in part, the potency to restore degenerated neuronal networks, transgenic high-dosage expression of neurotrophins by these cells in neurotransplantation may be advantageous. In the present study, a retroviral vector containing the gene of rat ciliary neurotrophic factor (rCNTF) was permanently transfected into a striatal neuronal progenitor cell line. Qualitative and quantitative analyses demonstrated a sustained expression of the transgene; i.e., rCNTF was present at the mRNA level and protein level. Moreover, cocultivation in separate chambers of transgenic CNTF-ST14A cells and CNTF-dependent TF1 cells exerted typical biological effects, such as increased proliferation and differentiation of the TF1 cells, indicating the functional integrity of the secreted recombinant neurotrophin. The CNTF-ST14A cells displayed improved stress response compared with native ST14A cells under differentiation conditions, i.e., at the nonpermissive temperature of 39 degrees C and after staurosporine exposure, respectively. This effect coincided with a relatively reduced apoptosis rate and a raised metabolic activity of CNTF-ST14A cells at 39 degrees C. Neurotransplantation of CNTF-ST14A cells in the rat quinolinic acid model of Huntington's disease showed a significant and sustained decline in pathological apomorphine-induced rotations compared with parental ST14A cells. We conclude that sustained functional transgene CNTF production improves stress response as well as metabolic activity, making CNTF-ST14A cells a promising tool for neurotransplantation in the quinolinic acid model of Huntington's disease.
Wheeler, V. C., L. A. Lebel, et al. (2003). "Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum." Hum Mol Genet 12(3): 273-81.
Somatic instability of expanded HD CAG repeats that encode the polyglutamine tract in mutant huntingtin has been implicated in the striatal selectivity of Huntington's disease (HD) pathology. Here in Hdh(Q111) mice, we have tested whether a genetic background deficient in Msh2, expected to eliminate the unstable behavior of the 109 CAG array inserted into the murine HD gene, would alter the timing or striatal specificity of a dominant disease phenotype that predicts late-onset neurodegeneration. Our analyses of Hdh(Q111/+):Msh2(+/+) and Hdh(Q111/+): Msh2(-/-) progeny revealed that, while inherited instability involved Msh2-dependent and -independent mechanisms, lack of Msh2 was sufficient to abrogate progressive HD CAG repeat expansion in striatum. The absence of Msh2 also eliminated striatal mutant huntingtin with somatically expanded glutamine tracts and caused an approximately 5 month delay in nuclear mutant protein accumulation, but did not alter the striatal specificity of this early phenotype. Thus, somatic HD CAG instability appears to be a consequence of a striatal-selective disease process that accelerates the timing of an early disease phenotype, via expansion of the glutamine tract in mutant huntingtin. Therefore Msh2, as a striking modifier of early disease onset in a precise genetic HD mouse model, provides a novel target for the development of pharmacological agents that aim to slow pathogenesis in man.
Wheelock, V. L., T. Tempkin, et al. (2003). "Predictors of nursing home placement in Huntington disease." Neurology 60(6): 998-1001.
OBJECTIVE: To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement. METHODS: Subjects were participants in the Huntington Study Group's Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using chi(2) and Student's t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used. RESULTS: Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents' average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p < 0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p < 0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement. CONCLUSIONS: Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.
Witjes-Ane, M. N., M. Vegter-Van Der Vlis, et al. (2003). "Cognitive and Motor Functioning in Gene Carriers for Huntington's Disease: A Baseline Study." J Neuropsychiatry Clin Neurosci 15(1): 7-16.
The aim of this study was to investigate the first changes in cognitive and motor functioning in Huntington's disease. Forty-six gene carriers, not clinically diagnosed for HD, were compared with 88 non-gene carriers. Gene carriers performed significantly worse on the Benton Visual Retention Test. This result was due to a minority of participants who had already developed cognitive impairment. Marginal differences appeared on the motor times of single reaction time measures after correction for motor signs. The findings are discussed in the context of inconsistencies in previous studies and underscore the need for longitudinal research.
Yazawa, I., N. Hazeki, et al. (2003). "Histone H3 is aberrantly phosphorylated in glutamine-repeat diseases." Biochem Biophys Res Commun 302(1): 144-9.
Double-labeling immunohistochemical studies staining with anti-ubiquitin and anti-phosphoserine antibodies and application of an enzymatic dephosphorylation technique reveal neuronal inclusions and affected nuclei to be aberrantly phosphorylated in brain tissues with patients with glutamine-repeat diseases. Regional distribution of the phosphorylated nuclei in neurons correlates with the pathology. To identify the target nuclear protein, transient expression of Huntington's disease exon 1 gene containing an expanded glutamine repeat was generated in a cell culture and nuclear inclusions were isolated with a fluorescence-activated cell sorting system. Immunoblotting studies of the aggregated nuclear proteins using anti-phosphoserine antibody demonstrate the protein of the aberrant phosphorylation as histone H3. The immunoblots of control and diseased brain tissues demonstrate that the phosphorylation of histone H3 is commonly increased in the diseased brains. Aberrant phosphorylation of histone H3 is surmised to be a shared pathological process in glutamine-repeat diseases.
Young, A. B. (2003). "Huntingtin in health and disease." J Clin Invest 111(3): 299-302.
Yu, Z. X., S. H. Li, et al. (2003). "Mutant Huntingtin Causes Context-Dependent Neurodegeneration in Mice with Huntington's Disease." J Neurosci 23(6): 2193-202.
Huntington's disease (HD) mouse models that express N-terminal huntingtin fragments show rapid disease progression and have been used for developing therapeutics. However, light microscopy reveals no significant neurodegeneration in these mice. It remains unclear how mutant huntingtin induces neurodegeneration. Using caspase staining, terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, and electron microscopy, we observed that N171-82Q mice, which express the first 171 aa of mutant huntingtin, displayed more degenerated neurons than did other HD mouse models. The neurodegeneration was also evidenced by increased immunostaining for glial fibrillary acidic protein and ultrastructural features of apoptosis. R6/2 mice, which express exon 1 of mutant huntingtin, showed dark, nonapoptotic neurons and degenerated mitochondria associated with mutant huntingtin. In HD repeat knock-in mice (HdhCAG150), which express full-length mutant huntingtin, degenerated cytoplasmic organelles were found in both axons and neuronal cell bodies in association with mutant huntingtin that was not labeled by an antibody to huntingtin amino acids 342-456. Transfection of cultured cells with mutant huntingtin revealed that an N-terminal huntingtin fragment (amino acids 1-208 plus a 120 glutamine repeat) caused a greater increase in caspase activity than did exon 1 huntingtin and longer huntingtin fragments. These results suggest that context-dependent neurodegeneration in HD may be mediated by different N-terminal huntingtin fragments. In addition, this study has identified neurodegenerative markers for the evaluation of therapeutic treatments in HD mouse models.
Zainelli, G. M., C. A. Ross, et al. (2003). "Transglutaminase cross-links in intranuclear inclusions in Huntington disease." J Neuropathol Exp Neurol 62(1): 14-24.
Cortical and striatal perinuclear cytoplasmic aggregates and intranuclear inclusions of mutant huntingtin are neuropathological hallmarks of Huntington disease (HD). Although the mechanisms involved in the formation of these aggregates are unclear, a recent hypothesis implicates cross-linking of mutant huntingtin protein into aggregates by transglutaminase. This study explores the hypothesis that transglutaminase catalyzes cross-linking of huntingtin into intranuclear inclusions. Using immunofluorescence and confocal microscopy we demonstrate 99% colocalization of transglutaminase-catalyzed epsilon-(gamma-glutamyl) lysine covalent cross-links with nuclear aggregates of huntingtin protein in the frontal cortex of postmortem HD brain tissue. Furthermore, the transglutaminase 2 isoform colocalizes with both huntingtin protein and epsilon-(gamma-glutamyl) lysine covalent cross-links in HD intranuclear inclusions. Transient transfection of N-terminally truncated huntingtin with an expanded glutamine domain (htt-N63-148Q-myc) with and without and transglutaminase 2 into HEK 293T cells resulted in an increase in cross-linked huntingtin in the insoluble formic acid-treated pellet in comparison to transfection of N-terminally truncated huntingtin with normal length glutamine domain (htt-N63-18Q-myc). Transfection with both htt-N63-148Q-myc and transglutaminase 2 resulted in high molecular weight huntingtin in the insoluble fraction. These data support the hypothesis that transglutaminase catalyzed cross-linking of mutant huntingtin is involved in the formation and/or stabilization of huntingtin protein aggregates in HD. Based on these and other studies, modulation of transglutaminase activity could be explored as a treatment for HD.
Zhou, F. M., C. Wilson, et al. (2003). "Muscarinic and nicotinic cholinergic mechanisms in the mesostriatal dopamine systems." Neuroscientist 9(1): 23-36.
The striatum and its dense dopaminergic innervation originating in the midbrain, primarily from the substantia nigra pars compacta and the ventral tegmental area, compose the mesostriatal dopamine (DA) systems. The nigrostriatal system is involved mainly in motor coordination and in disorders such as Tourette's syndrome, Huntington's disease, and Parkinson's disease. The dopaminergic projections from the ventral tegmental area to the striatum participate more in the processes that shape behaviors leading to reward, and addictive drugs act upon this mesolimbic system. The midbrain DA areas receive cholinergic innervation from the pedunculopontine tegmentum and the laterodorsal pontine tegmentum, whereas the striatum receives dense cholinergic innervation from local interneurons. The various neurons of the mesostriatal systems express multiple types of muscarinic and nicotinic acetylcholine receptors as well as DA receptors. Especially in the striatum, the dense mingling of dopaminergic and cholinergic constituents enables potent interactions. Evidence indicates that cholinergic and dopaminergic systems work together to produce the coordinated functioning of the striatum. Loss of that cooperative activity contributes to the dysfunction underlying Parkinson's disease.