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Huntington's Disease Reviews: 2003

(24 References)

Bates, G. (2003). "Huntingtin aggregation and toxicity in Huntington's disease." Lancet 361(9369): 1642-4.

            CONTEXT: Huntington's disease is a late onset neurodegenerative disorder for which the mutation is a CAG/polyglutamine (polyQ) repeat expansion in the gene encoding the huntingtin protein. The disease is one of nine inherited neurodegenerative disorders that are caused by this type of mutation, and which include dentatorubral pallidoluysian atrophy, spinal and bulbar muscular atrophy, and the spinocerebellar ataxias 1, 2, 3, 6, 7, and 17. The mutant proteins are unrelated except for the polyQ tract, and aggregated polyQ is a major component of the proteinaceous deposits that are found in patients' brains for all of these diseases. STARTING POINT: Since the discovery of polyQ aggregates, the proposed role of the aggregation process has ranged from being central to disease pathogenesis, to a benign epiphenomenon, or even to being neuroprotective. Attempts to correlate the presence of aggregates with the onset of phenotype have been complicated by the difficulties in detecting and quantifying small aggregated forms of polyQ, and because all possible structural conformers of the repeat are present in the system under analysis. A paper by W Yang and colleagues (Hum Mol Genet 2002; 11: 2905-17) circumvents these limitations and demonstrates that preformed polyQ aggregates are highly toxic when directed to the cell nucleus. Consistent with aggregate toxicity, pharmacological intervention aimed at inhibiting aggregate formation has recently shown beneficial effects in a mouse model of Huntington's disease (I Sanchez and colleagues, Nature 2003; 421: 373-79). WHERE NEXT: The demonstration that polyQ aggregates are toxic is important because it further validates polyQ aggregation as a therapeutic target. To exploit this finding fully, greater understanding of the formation and structure of polyQ aggregates is needed. However, even without this knowledge, establishing high-throughput screens to identify aggregation inhibitors has been straightforward, and early in-vivo experiments that target aggregation have been promising. As the molecular events that contribute to the early stages of the pathogenesis of Huntington's disease are uncovered, such events will be developed as therapeutic targets. The inhibition of huntingtin aggregation should be a major focus in this effort and the practicalities of this approach are likely to unfold over the next 5-10 years.

 

Beal, M. F. (2003). "Bioenergetic approaches for neuroprotection in Parkinson's disease." Ann Neurol 53 Suppl 3: S39-47; discussion S47-8.

            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.

 

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.

 

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.

 

Choi, I. Y., S. P. Lee, et al. (2003). "In vivo NMR studies of neurodegenerative diseases in transgenic and rodent models." Neurochem Res 28(7): 987-1001.

            In vivo magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) provide unique quality to attain neurochemical, physiological, anatomical, and functional information non-invasively. These techniques have been increasingly applied to biomedical research and clinical usage in diagnosis and prognosis of diseases. The ability of MRS to detect early yet subtle changes of neurochemicals in vivo permits the use of this technology for the study of cerebral metabolism in physiological and pathological conditions. Recent advances in MR technology have further extended its use to assess the etiology and progression of neurodegeneration. This review focuses on the current technical advances and the applications of MRS and MRI in the study of neurodegenerative disease animal models including amyotrophic lateral sclerosis, Alzheimer's, Huntington's, and Parkinson's diseases. Enhanced MR measurable neurochemical parameters in vivo are described in regard to their importance in neurodegenerative disorders and their investigation into the metabolic alterations accompanying the pathogenesis of neurodegeneration.

 

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.

 

Friedlander, R. M. (2003). "Apoptosis and caspases in neurodegenerative diseases." N Engl J Med 348(14): 1365-75.

           

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.

 

Hashimoto, R., K. Fujimaki, et al. (2003). "[Neuroprotective actions of lithium]." Seishin Shinkeigaku Zasshi 105(1): 81-6.

            Lithium has long been one of the primary drugs used to treat bipolar mood disorder. However, neither the etiology of this disease nor the therapeutic mechanism(s) of this drug is well understood. Several lines of clinical evidence suggest that lithium has neurotrophic actions. For example chronic lithium treatment increases the volume of gray matter and the content of N-acetyl-aspartate, a cell survival marker, in bipolar mood disorder patients (Moore et al., 2000). Moreover, treatment with this mood-stabilizer suppresses the decrease in the volume of the subgenual pre-frontal cortex found in bipolar patients (Drevets, 2001). To elucidate molecular mechanisms underlying the neuroprotective and neurotrophic actions of lithium, we employed a preparation of cultured cortical neurons prepared form embryonic rats. We found that treatment with therapeutic doses (0.2-1.2 mM) of lithium robustly protects cortical neurons from multiple insults, notably glutamate-induced excitotoxicity. The neuroprotection against glutamate excitotoxicity is time-dependent, requiring treatment for 5-6 days for maximal effect, and is associated with a reduction in NMDA receptor-mediated Ca2+ influx. The latter is correlated with a decrease in Tyrosine 1472 phosphorylation levels in the NR2B subunit of NMDA receptors and a loss of Src kinase activity which is involved in NR2B tyrosine phosphorylation. Neither the activity of total tyrosine protein kinase nor that of tyrosine protein phosphatase is affected by this drug, indicating the selectivity of the modulation. Lithium neuroprotection against excitotoxicity is inhibited by a BDNF-neutralizing antibody and K252a, a Trk antagonist. Lithium treatment time-dependently increases the intracellular level of BDNF in cortical neurons and activates its receptor, TrkB. The neuroprotection can be completely blocked by either heterozygous or homozygous knockout of the BDNF gene. These results suggest a central role of BDNF and TrkB in mediating the neuroprotective effects of this mood-stabilizer. Finally, long-term lithium treatment of cortical neurons stimulates the proliferation of their progenitor cells detected by co-labeling with BrdU and nestin. Lithium pretreatment also blocks the decrease in progenitor proliferation induced by glutamate, glucocorticoids and haloperidol, suggesting a role in CNS neuroplasticity. We used animal models to investigate further therapeutic potentials for lithium. In the MCAO/reperfusion model of stroke, we found that post-insult treatment with lithium robustly reduced infarct volume and neurological deficits. These beneficial effects were evident when therapeutic concentrations of lithium were injected at least up to 3 h after ischemic onset. The neuroprotection was associated with activation of heat-shock factor-1 and induction of heat-shock protein-70, a cytoprotective protein. In a rat excitotoxic model of Huntington's disease, the excitotoxin-induced loss of striatal medium-sized neurons was markedly reduced by lithium. This lithium protection was correlated with up-regulation of cytoprotective Bcl-2 and down-regulation of apoptotic proteins p53 and Bax, and neurons showing DNA damage and caspase-3 activation. Taken together, our results provide a new insight into the molecular mechanisms involved in lithium neuroprotection against glutamate excitotoxicity. Moreover, these novel molecular and cellular actions might contribute to the neurotrophic and neuroprotective actions of this mood-stabilizer in patients, and could be related to its clinical efficacy for treating mood disorder patients. Clearly, mood-stabilizers may have expanded use for treating excitotoxin-related neurodegenerative diseases.

 

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.

 

Kakishita, K., N. Nakao, et al. (2003). "[Restoration of brain function by cell transplantation]." Nippon Rinsho 61(3): 457-62.

            The first trial of restoring brain functions with cell grafting was performed in 1979 using a rat model of Parkinson's disease. Fetal nigral tissue was demonstrated to survive grafted tissue and to repair motor dysfunction in the model rat. The encouraging results indicate that cell transplantation may be useful to restore brain functions in neurodegenerative disorders in which a certain type of neuronal populations is specifically damaged. This review article discussed the possibility of cell transplantation therapy in several neurodegenerative disorders, such as Parkinson's disease, Huntington's disease and Alzheimer's disease.

 

Lythgoe, M. F., N. R. Sibson, et al. (2003). "Neuroimaging of animal models of brain disease." Br Med Bull 65: 235-57.

            The main aim of this review is to describe some of the many animal models that have proved to be valuable from a neuroimaging perspective. This paper complements other articles in this volume, with a focus on animal models of the pathology of human brain disorders for investigations with modern non-invasive neuroimaging techniques. The use of animal model systems forms a fundamental part of neuroscience research efforts to improve the prevention, diagnosis, understanding and treatment of neurological conditions. Without such models it would be impossible to investigate such topics as the underlying mechanisms of neuronal cell damage and death, or to screen compounds for possible anticonvulsant properties. The adequacy of any one particular model depends on the suitability of information gained during experimental conditions. It is important, therefore, to understand the various types of animal model available and choose an appropriate model for the research question.

 

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.

 

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.

 

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.

 

Shastry, B. S. (2003). "Neurodegenerative disorders of protein aggregation." Neurochem Int 43(1): 1-7.

            In recent years, it has become increasingly clear that many neurodegenerative diseases involve aggregation and deposition of misfolded proteins such as amyloid beta, tau, alpha-synuclein and polyglutamine containing proteins. This abnormal deposition of misfolded proteins produce malfunctioning of a distinctive set of neurons. It may also induce oxidative and endoplasmic reticulum stress and proteosomal and mitochondrial dysfunction that ultimately leads to neuronal death. While hereditary forms of disorders are caused by genetic mutations, many sporadic cases are likely to be due to genetic and environmental factors. These disorders are progressive in nature. Therefore, treatment is difficult. However, for some diseases, a growing number of treatment options such as drugs, antioxidants, cell transplantation, surgery, rehabilitation procedures and preimplantation diagnosis is available. It should be noted that many of these treatments produce unacceptable risks or adverse effects and they are of only minimal benefit for patients. In future, an understanding of the causes of protein aggregation and genetic and environmental susceptibility factors of a specific individual (or specific individual determinants) may provide a better opportunity for an effective therapeutic intervention.

 

SuttonBrown, M. and O. Suchowersky (2003). "Clinical and research advances in Huntington's disease." Can J Neurol Sci 30 Suppl 1: S45-52.

            Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by abnormalities of movement and dementia. No curative treatment is available and HD results in gradually increasing disability. Characterization of the genetic abnormality has dramatically increased our understanding of the underlying mechanisms of the disease process, and has resulted in the development of a number of genetic models. These research tools are forming the basis of advanced work into the diagnosis, pathophysiology, and potential treatment of the disease. Clinically, the availability of genetic testing has eased confirmation of diagnosis in symptomatic individuals. Presymptomatic testing allows at-risk individuals to make informed choices but requires supportive care from physicians. Current clinical treatment is focused on symptom control. Advances in research have resulted in the development of potential neuroprotective strategies which are undergoing clinical testing.

 

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.

           

Vila, M. and S. Przedborski (2003). "Targeting programmed cell death in neurodegenerative diseases." Nat Rev Neurosci 4(5): 365-75.

           

Young, A. B. (2003). "Huntingtin in health and disease." J Clin Invest 111(3): 299-302.

           

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.

           

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