Back
to
Literature Database
Enhanced by
Neuroinformation
Neurodegeneration Reviews
(57 References)
Aruoma, O. I. (2003). "Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods." Mutat Res 523-524: 9-20.
The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Downs syndrome) and aging challenges continue to emerge from difficulties associated with methods used in evaluating antioxidant actions in vivo. Our interest presently is focused on development of neurodegeneration models based on the integrity of neuronal cells in the central nervous system and how they are protected by antioxidants when challenged by neurotoxins as well as Fenton chemistry models based on the profile of polyunsaturated fatty acids (PUFAs) for the assessment of antioxidant actions in vivo. Use continues to be made of several in vitro analytical tools to characterise the antioxidant propensity of bioactive compounds in plant foods and supplements. For example, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), total oxidant scavenging capacity (TOSC), the deoxyribose assay, assays involving oxidative DNA damage, assays involving reactive nitrogen intermediates (e.g. ONOO(-)), Trolox equivalent antioxidant capacity (TEAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. There is need to agree governance on in vitro antioxidant methods based on an understanding of the mechanisms involved. Because some of the assays are done in non-physiological pH values, it is impossible to extrapolate the results to physiological environment. The consensus of opinion is that a mix of these tools should be used in assessing the antioxidant activities in vitro. The proof of bio-efficacy must emanate from application of reliable in vivo models where markers of baseline oxidative damage are examined from the standpoint of how they are affected by changes in diet or by antioxidant supplements.
Baker, D. and D. J. Hankey (2003). "Gene therapy in autoimmune, demyelinating disease of the central nervous system." Gene Ther 10(10): 844-53.
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), where suspected autoimmune attack causes nerve demyelination and progressive neurodegeneration and should benefit from both anti-inflammatory and neuroprotective strategies. Although neuroprotection strategies are relatively unexplored in MS, systemic delivery of anti-inflammatory agents to people with MS has so far been relatively disappointing. This is most probably because of the limited capacity of these molecules to enter the target tissue, because of exclusion by the blood-brain barrier. The complex natural history of MS also means that any therapeutic agents will have to be administered long-term. Gene therapy offers the possibility of site-directed, long-term expression, and is currently being preclinically investigated in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. While some immune effects may be targeted in the periphery using DNA vaccination, strategies both viral and nonviral are being developed to target agents into the CNS either via direct delivery or using the trafficking properties of cell-carrier systems. Targeting of leucocyte activation, cytokines and nerve growth factors have shown some promising benefit in animal EAE systems, the challenge will be their application in clinical use.
Baker, D. and G. Pryce (2003). "The therapeutic potential of cannabis in multiple sclerosis." Expert Opin Investig Drugs 12(4): 561-7.
There has been renewed interest in the therapeutic applications of cannabis, and people, particularly those with multiple sclerosis, claim that it may offer benefit in symptom control. Cannabis exerts many of its effects because it taps into an endogenous cannabinoid system. Recent advances have begun to shine light on the biology of this system and may support some of the anecdotal medical claims. The problem with cannabis as a drug is that both the positive and negative aspects are largely the work of the same receptor. However, it may be possible to avoid these through modulation of the endogenous system. Cannabinoids provide a novel therapeutic target, not only for controlling symptoms, but also slowing disease progression through inhibition of neurodegeneration, which is the cause of accumulating irreversible disability.
Barber, A. J. (2003). "A new view of diabetic retinopathy: a neurodegenerative disease of the eye." Prog Neuropsychopharmacol Biol Psychiatry 27(2): 283-90.
Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of legal blindness in working-age adults. The clinical hallmarks of DR include increased vascular permeability, leading to edema, and endothelial cell proliferation. Much of the research effort has been focused on vascular changes, but it is becoming apparent that other degenerative changes occur beyond the vascular cells of the retina. These include increased apoptosis, glial cell reactivity, microglial activation, and altered glutamate metabolism. When occurring together, these changes may be considered as neurodegenerative and could explain some of the functional deficits in vision that begin soon after the onset of diabetes.This review will present the current evidence that neurodegeneration of the retina is a critical component of DR. There are two basic hypotheses that account for loss of cells in the neural retina. First, the loss of blood-retinal barrier integrity, which initially manifests as an increase in vascular permeability, causes a failure to control the composition of the extracellular fluid in the retina, which in turn leads to edema and neuronal cell loss. Alternatively, diabetes has a direct effect on metabolism within the neural retina, leading to an increase in apoptosis, which in turn causes breakdown of the blood-retinal barrier. It is not clear which hypothesis will be found to be correct, and, in fact, it is likely that vascular permeability and neuronal apoptosis are closely linked components of DR. However, the gradual loss of neurons suggests that progress of the disease is ultimately irreversible, since these cells cannot usually be replaced. In light of this possibility, new treatments for DR should be preventive in nature, being implemented before overt clinical symptoms develop. While vascular permeability is the target that is primarily considered for new treatments of DR, evidence presented here suggests that apoptosis of neurons is also an essential target for pharmacological studies. The vision of people with diabetes will be protected only when we have discovered a means to prevent the gradual but constant loss of neurons within the inner retina.
Barmak, K., E. Harhaj, et al. (2003). "Human T cell leukemia virus type I-induced disease: pathways to cancer and neurodegeneration." Virology 308(1): 1-12.
Retroviral infection is associated with a number of pathologic abnormalities, including a variety of cancers, immunologic diseases, and neurologic disorders. Shortly after its discovery in 1980, human T cell leukemia virus type I (HTLV-I) was found to be the etiologic agent of both adult T cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurologic disease characterized by demyelinating lesions in both the brain and the spinal cord. Approximately 5-10% of HTLV-I-infected individuals develop either ATL or HAM/TSP. Interestingly, the two diseases have vastly different pathologies and have rarely been found to occur within the same individual. While a number of host and viral factors including virus strain, viral load, and HLA haplotype have been hypothesized to influence disease outcome associated with HTLV-I infection, the relative contributions of such factors to disease pathogenesis have not been fully established. Recent research has suggested that the route of primary viral infection may dictate the course of disease pathogenesis associated with HTLV-I infection. Specifically, mucosal exposure to HTLV-I has been associated with cases of ATL, while primary viral infection based in the peripheral blood has been correlated with progression to HAM/TSP. However, the cellular and molecular mechanisms regulating disease progression resulting from primary viral invasion remain to be elucidated. Although a variety of factors likely influence these mechanisms, the differential immune response mounted by the host against the incoming virus initiated in either the peripheral blood or the mucosal compartments likely plays a key role in determining the outcome of HTLV-I infection. It has been proposed that the route of infection and size of the initial viral inoculum allows HTLV-I to infect different target cell populations, in turn influencing the breadth of the immune response mounted against HTLV-I and affecting disease pathogenesis. A model of HTLV-I-induced disease progression is presented, integrating information regarding the role of several host and viral factors in the genesis of both neoplasia and neurologic disease induced following HTLV-I infection, focusing specifically on differential viral invasion into the bone marrow (BM) and the influence of this event on the virus-specific CD8(+) cytotoxic T lymphocyte (CTL) response that is initiated following HTLV-I infection.
Bjartmar, C., J. R. Wujek, et al. (2003). "Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease." J Neurol Sci 206(2): 165-71.
Axonal degeneration has been identified as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory demyelination influences axon pathology during relapsing-remitting MS (RR-MS). This axonal loss remains clinically silent for many years, and irreversible neurological disability develops when a threshold of axonal loss is reached and compensatory CNS resources are exhausted. Experimental support for this view-the axonal hypothesis-is provided by data from various animal models with primary myelin or axonal pathology, and from pathological or magnetic resonance studies on MS patients. In mice with experimental autoimmune encephalomyelitis (EAE), 15-30% of spinal cord axons can be lost before permanent ambulatory impairment occurs. During secondary progressive MS (SP-MS), chronically demyelinated axons may degenerate due to lack of myelin-derived trophic support. In addition, we hypothesize that reduced trophic support from damaged targets or degeneration of efferent fibers may trigger preprogrammed neurodegenerative mechanisms. The concept of MS as an inflammatory neurodegenerative disease has important clinical implications regarding therapeutic approaches, monitoring of patients, and the development of neuroprotective treatment strategies.
Blasko, I. and B. Grubeck-Loebenstein (2003). "Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease." Drugs Aging 20(2): 101-13.
The dysregulation in the metabolism of beta-amyloid precursor protein and consequent deposition of amyloid-beta (Abeta) has been envisaged as crucial for the development of neurodegeneration in Alzheimer's disease (AD). Amyloid deposition begins 10-20 years before the appearance of clinical dementia. During this time, the brain is confronted with increasing amounts of toxic Abeta peptides and data from the last decade intriguingly suggest that both the innate and the adaptive immune systems may play an important role in the disorder. Innate immunity in the brain is mainly represented by microglial cells, which phagocytose and degrade Abeta. As the catabolism of Abeta decreases, glial cells become overstimulated and start to produce substances that are toxic to neurons, such as nitric oxide and inflammatory proteins. Pro-inflammatory cytokines can be directly toxic or stimulate Abeta production and increase its cytotoxicity. A therapeutic possibility arises from clinical studies, which demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset and slow the progression of AD. Recent data show that in addition to the suppression of inflammatory processes in the brain NSAIDs may decrease the production of Abeta peptides. The role of adaptive immunity lies mainly in the fact that Abeta can be recognised as an antigen. Immunisation with Abeta peptides and peripheral administration of Abeta-specific antibodies both decrease senile plaques and cognitive dysfunction in murine models of AD. A recent trial in humans seems still to be hampered by adverse effects. As adaptive immunity decreases with aging while innate immunity remains intact, immunotherapy for AD will have to be adapted to this situation. Strategies that combine vaccination and inflammatory drug treatment could be considered.
Butler, T. L., C. A. Kassed, et al. (2003). "Signal transduction and neurosurvival in experimental models of brain injury." Brain Res Bull 59(5): 339-51.
Brain injury and neurodegenerative disease are linked by their primary pathological consequence-death of neurons. Current approaches for the treatment of neurodegeneration are limited. In this review, we discuss animal models of human brain injury and molecular biological data that have been obtained from their analysis. In particular, signal transduction pathways that are associated with neurosurvival following injury to the brain are presented and discussed.
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.
Conway, K. A., E. W. Baxter, et al. (2003). "Emerging beta-amyloid therapies for the treatment of Alzheimer's disease." Curr Pharm Des 9(6): 427-47.
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of beta-amyloid peptide (Abeta) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but do not modify the progression of the disease. The etiology of AD is unclear. However, data from familial AD mutations (FAD) strongly support the "amyloid cascade hypothesis" of AD, i.e. that neurodegeneration in AD is initiated by the formation of neurotoxic beta-amyloid (Abeta) aggregates; all FAD mutations increase levels of Abeta peptide or density of Abeta deposits. The likely link between Abeta aggregation and AD pathology emphasizes the need for a better understanding of the mechanisms of Abeta production. This review summarizes current therapeutic strategies directed at lowering Abeta levels and decreasing levels of toxic Abeta aggregates through (1) inhibition of the processing of amyloid precursor protein (APP) to Abeta peptide, (2) inhibition, reversal or clearance of Abeta aggregation, (3) cholesterol reduction and (4) Abeta immunization.
Cookson, M. R. (2003). "Parkin's substrates and the pathways leading to neuronal damage." Neuromolecular Med 3(1): 1-13.
CDATA[Mutations in the Parkin gene are associated with Parkinson s disease (PD). The gene product has been shown to be an E3 protein-ubiquitin ligase, catalyzing the addition of ubiquitin to target proteins prior to their destruction via the proteasome. This activity is thus key in regulating the turnover of substrate proteins. A predictive hypothesis for how this results in PD is that the misregulation of proteasomal degradation of Parkin s substrates is deleterious to neurons. Several different laboratories have identified alternate candidate proteins. In this review, the likelihood of each of the proposed substrates for parkin being robust will be evaluated. The distribution and abundance of the proteins will be examined for clues as to which are the pathologically important substrates for parkin. The possibility that loss of regulation of turnover of one or more of these substrates contributes to the selective neurodegeneration seen in PD is also discussed.
Dineley, K. E., T. V. Votyakova, et al. (2003). "Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration." J Neurochem 85(3): 563-70.
An increasing body of evidence suggests that high intracellular free zinc promotes neuronal death by inhibiting cellular energy production. A number of targets have been postulated, including complexes of the mitochondrial electron transport chain, components of the tricarboxylic acid cycle, and enzymes of glycolysis. Consequences of cellular zinc overload may include increased cellular reactive oxygen species (ROS) production, loss of mitochondrial membrane potential, and reduced cellular ATP levels. Additionally, zinc toxicity might involve zinc uptake by mitochondria and zinc induction of mitochondrial permeability transition. The present review discusses these processes with special emphasis on their potential involvement in brain injury.
Dolezal, V. and J. Kasparova (2003). "Beta-amyloid and cholinergic neurons." Neurochem Res 28(3-4): 499-506.
It is generally accepted that the crucial events in the pathogeny of Alzheimer's disease (AD) are the increased accumulation of amyloidogenic peptides derived from amyloid precursor protein and the harmful actions of these peptides on neurons, which bring about neurodegeneration. The enhanced beta-amyloid accumulation is known to be caused by mutations of specific genes in patients who suffer from the familial (hereditary) form of AD but who represent just a minor group within the total population of AD patients. The reasons for beta-amyloid accumulation are not known in the much larger group of patients with the sporadic form of the disease. A biochemical feature common to either form of the disease is the preferential atrophy and degeneration of cholinergic neurons, which is probably responsible for much of the cognitive decline characteristic of the disease. We present an overview of recent investigations on the interactions between beta-amyloid and cholinergic neurons.
Driscoll, M. and B. Gerstbrein (2003). "Dying for a cause: invertebrate genetics takes on human neurodegeneration." Nat Rev Genet 4(3): 181-94.
If invertebrate neurons are injured by hostile environments or aberrant proteins they die much like human neurons, indicating that the powerful advantages of invertebrate molecular genetics might be successfully used for testing specific hypotheses about human neurological diseases, for drug discovery and for non-biased screens for suppressors and enhancers of neurodegeneration. Recent molecular dissection of the genetic requirements for hypoxia, excitotoxicity and death in models of Alzheimer disease, polyglutamine-expansion disorders, Parkinson disease and more, is providing mechanistic insights into neurotoxicity and suggesting new therapeutic interventions. An emerging theme is that neuronal crises of distinct origins might converge to disrupt common cellular functions, such as protein folding and turnover.
Engidawork, E. and G. Lubec (2003). "Molecular changes in fetal Down syndrome brain." J Neurochem 84(5): 895-904.
Trisomy of human chromosome 21 is a major cause of mental retardation and other phenotypic abnormalities collectively known as Down syndrome. Down syndrome is associated with developmental failure followed by processes of neurodegeneration that are known to supervene later in life. Despite a widespread interest in Down syndrome, the cause of developmental failure is unclear. The brain of a child with Down syndrome develops differently from that of a normal one, although characteristic morphological differences have not been noted in prenatal life. On the other hand, a review of the existing literature indicates that there are a series of biochemical alterations occurring in fetal Down syndrome brain that could serve as substrate for morphological changes. We propose that these biochemical alterations represent and/or precede morphological changes. This review attempts to dissect these molecular changes and to explain how they may lead to mental retardation.
Feldman, E. L. (2003). "Oxidative stress and diabetic neuropathy: a new understanding of an old problem." J Clin Invest 111(4): 431-3.
Gandy, S. (2003). "Estrogen and neurodegeneration." Neurochem Res 28(7): 1003-8.
Although estrogen is best known for its effects on the maturation and differentiation of the primary and secondary sex organs, increasing evidence suggests that its influence extends beyond this system, and its activity in the CNS may initiate, or influence our susceptibility to neurodegenerative decline. Estrogen has been proposed to act as a neuroprotectant at several levels, and it is probable that deprivation of estrogen as a result of menopause exposes the aging or diseased brain to several insults. In addition, estrogen deprivation is likely to initiate or enhance degenerative changes caused by oxidative stress, and to reduce the brain's ability to maintain synaptic connectivity and cholinergic integrity leading to the cognitive decline seen in aged and disease-afflicted individuals.
Grossman, A. W., J. D. Churchill, et al. (2003). "Experience effects on brain development: possible contributions to psychopathology." J Child Psychol Psychiatry 44(1): 33-63.
Researchers and clinicians are increasingly recognizing that psychological and psychiatric disorders are often developmentally progressive, and that diagnosis often represents a point along that progression that is defined largely by our abilities to detect symptoms. As a result, strategies that guide our searches for the root causes and etiologies of these disorders are beginning to change. This review describes interactions between genetics and experience that influence the development of psychopathologies. Following a discussion of normal brain development that highlights how specific cellular processes may be targeted by genetic or environmental factors, we focus on four disorders whose origins range from genetic (fragile X syndrome) to environmental (fetal alcohol syndrome) or a mixture of both factors (depression and schizophrenia). C.H. Waddington's canalization model (slightly modified) is used as a tool to conceptualize the interactive influences of genetics and experience in the development of these psychopathologies. Although this model was originally proposed to describe the 'canalizing' role of genetics in promoting normative development, it serves here to help visualize, for example, the effects of adverse (stressful) experience in the kindling model of depression, and the multiple etiologies that may underlie the development of schizophrenia. Waddington's model is also useful in understanding the canalizing influence of experience-based therapeutic approaches, which also likely bring about 'organic' changes in the brain. Finally, in light of increased evidence for the role of experience in the development and treatment of psychopathologies, we suggest that future strategies for identifying the underlying causes of these disorders be based less on the mechanisms of action of effective pharmacological treatments, and more on increased knowledge of the brain's cellular mechanisms of plastic change.
Gupta, N. and Y. H. Yucel (2003). "Brain changes in glaucoma." Eur J Ophthalmol 13 Suppl 3: S32-5.
There is evidence that glaucomatous damage extends from retinal ganglion cells to vision centers in the brain. In the lateral geniculate nucleus (LGN), the major relay center between the eye and the visual cortex, neurons should undergo degenerative and/or neurochemical changes in magno-, parvo-, and koniocellular pathways conveying motion, red-green, and blue-yellow information, respectively. Furthermore, in both the LGN and visual cortex in glaucoma, changes in metabolic activity are observed. The study of brain changes in glaucoma may provide new insights into the pathobiology of glaucomatous damage and disease progression, and may stimulate new detection and therapeutic strategies to prevent blindness.
Hayflick, S. J. (2003). "Pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome)." J Neurol Sci 207(1-2): 106-7.
Huang, Z., R. de la Fuente-Fernandez, et al. (2003). "Etiology of Parkinson's disease." Can J Neurol Sci 30 Suppl 1: S10-8.
There is growing recognition that Parkinson's disease (PD) is likely to arise from the combined effects of genetic predisposition as well as largely unidentified environmental factors. The relative contribution of each varies from one individual to another. Even in situations where more than one family member is affected, the predominant influence may be environmental. Although responsible for only a small minority of cases of PD, recently identified genetic mutations have provided tremendous insights into the basis for neurodegeneration and have led to growing recognition of the importance of abnormal protein handling in Parkinson's as well as other neurodegenerative disorders. Abnormal protein handling may increase susceptibility to oxidative stress; conversely, numerous other factors, including oxidative stress and impaired mitochondrial function can lead to impaired protein degradation. A limited number of environmental factors are known to be toxic to the substantia nigra; in contrast, some factors such as caffeine intake and cigarette smoking may protect against the development of PD, although the mechanisms are not established. We review the various genetic and environmental factors thought to be involved in PD, as well as the mechanisms that contribute to selective nigral cell death.
Hunot, S. and E. C. Hirsch (2003). "Neuroinflammatory processes in Parkinson's disease." Ann Neurol 53 Suppl 3: S49-58; discussion S58-60.
Parkinson's disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, its cause remains unknown and the mechanism of nerve cell death uncertain. Apart from the massive loss of dopaminergic neurons, PD brains also show a conspicuous glial reaction together with signs of a neuroinflammatory reaction manifested by elevated cytokine levels and upregulation of inflammatory-associated factors such as cyclooxygenase-2 and inducible nitric oxide synthase. Mounting evidence also suggests a possible deleterious effect of these neuroinflammatory processes in experimental models of the disease. We propose that, in PD, neuroinflammation plays a role in the cascade of events leading to nerve cell death, thus propagating the neurodegenerative process. In this review, we summarize and discuss the latest findings regarding neuroinflammatory aspects in PD.
Isacson, O., L. M. Bjorklund, et al. (2003). "Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells." Ann Neurol 53 Suppl 3: S135-46; discussion S146-8.
New therapeutic nonpharmacological methodology in Parkinson's disease (PD) involves cell and synaptic renewal or replacement to restore function of neuronal systems, including the dopaminergic (DA) system. Using fetal DA cell therapy in PD patients and laboratory models, it has been demonstrated that functional motor deficits associated with parkinsonism can be reduced. Similar results have been observed in animal models with stem cell-derived DA neurons. Evidence obtained from transplanted PD patients further shows that the underlying disease process does not destroy transplanted fetal DA cells, although degeneration of the host nigrostriatal system continues. The optimal DA cell regeneration system would reconstitute a normal neuronal network capable of restoring feedback-controlled release of DA in the nigrostriatal system. The success of cell therapy for PD is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra pars compacta as well as the technical and surgical steps associated with the transplantation procedure. Recent laboratory work has focused on using stem cells as a starting point for deriving the optimal DA cells to restore the nigrostriatal system. Ultimately, understanding the cell biological principles necessary for generating functional DA neurons can provide many new avenues for better treatment of patients with PD.
Ischiropoulos, H. and J. S. Beckman (2003). "Oxidative stress and nitration in neurodegeneration: cause, effect, or association?" J Clin Invest 111(2): 163-9.
Jenner, P. (2003). "Oxidative stress in Parkinson's disease." Ann Neurol 53 Suppl 3: S26-36; discussion S36-8.
Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to, or is a consequence of, these events. Oxidative damage to lipids, proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as 4-hydroxynonenal (HNE), can react with proteins to impair cell viability. There is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. Recently, altered ubiquitination and degradation of proteins have been implicated as key to dopaminergic cell death in PD. Oxidative stress can impair these processes directly, and products of oxidative damage, such as HNE, can damage the 26S proteasome. Furthermore, impairment of proteasomal function leads to free radical generation and oxidative stress. Oxidative stress occurs in idiopathic PD and products of oxidative damage interfere with cellular function, but these form only part of a cascade, and it is not possible to separate them from other events involved in dopaminergic cell death.
Kitamura, Y. and Y. Nomura (2003). "Stress proteins and glial functions: possible therapeutic targets for neurodegenerative disorders." Pharmacol Ther 97(1): 35-53.
Recent findings suggest that unfolded or misfolded proteins participate in the pathology of several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Usually, several stress proteins and glial cells act as intracellular molecular chaperones and show chaperoning neuronal function, respectively. In the brains of patients with neurodegenerative disorders, however, stress proteins are expressed and frequently associated with protein aggregates, and glial cells are activated around degenerative regions. In addition, several stress proteins and glial cells may also regulate neuronal cell death and loss. Therefore, some types of stress proteins and glial cells are considered to be neuroprotective targets. We summarize the current findings regarding the neuroprotective effects of stress proteins and glial cells, and discuss the possibility of using this knowledge to develop new therapeutic strategies to treat neurodegeneration.
Klein, J. A. and S. L. Ackerman (2003). "Oxidative stress, cell cycle, and neurodegeneration." J Clin Invest 111(6): 785-93.
Konradi, C. and S. Heckers (2003). "Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment." Pharmacol Ther 97(2): 153-79.
The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.
Kroemer, G. (2003). "Mitochondrial control of apoptosis: an introduction." Biochem Biophys Res Commun 304(3): 433-5.
Mitochondrial membrane permeabilization [MMP] constitutes an essential step of the intrinsic pathway leading to apoptosis. Several oncoproteins, tumor suppressor gene products, viral virulence factors and pharmacological agents modulate apoptosis via direct effects on mitochondria. This has far-reaching implications for the pathophysiology of several major diseases such as cancer, neurodegeneration, and AIDS. The detailed investigation of the mechanisms of MMP will hopefully lead to the discovery of suitable drug targets for therapeutic intervention on cell death control.
Kruttgen, A., S. Saxena, et al. (2003). "Neurotrophins and neurodegenerative diseases: receptors stuck in traffic?" J Neuropathol Exp Neurol 62(4): 340-50.
Neurotrophins are well known for their physiological role as key modulators of neuronal survival, neurite out-growth, and synaptic connectivity during development and into adulthood. Moreover, neurotrophins are potent agents, ameliorating neuronal degeneration in many model systems for neurological diseases. However, a causal role for mutations in neurotrophins or neurotrophin receptors in human neurodegenerative diseases has been largely lacking. As neurotrophin receptors are located at synapses and as their signaling involves the neuronal nucleus, they need to bridge tantalizing distances in order to retrogradely communicate their survival signals. On the other hand, anterogradely transported neurotrophins are released at the synapse and act on postsynaptic cells. Antero- and retrograde signaling and trafficking is an emerging focus of interest in neurotrophin research. Some neurodegenerative diseases are known to affect transport of organelles. Thus, it appears likely that neurodegeneration could be caused by "indirect" effects on neurotrophin trafficking and, hence, signaling. In this review we summarize recent work on neurotrophins in neurodegenerative diseases with special focus on possible implications of disturbed trafficking of organelles and retrograde axonal signaling.
Lev, N., E. Melamed, et al. (2003). "Apoptosis and Parkinson's disease." Prog Neuropsychopharmacol Biol Psychiatry 27(2): 245-50.
Parkinson's disease (PD) is a severe and progressive neurodegenerative disease. It is the second most common neurodegenerative disease, after Alzheimer's disease. It is caused by the selective loss of the dopaminergic neurons in the substantia nigra (SN) pars compacta. Although subject to intensive research, the etiology of PD is still enigmatic and treatment is basically symptomatic. Many factors are thought to operate in the mechanism of cell death of the nigrostriatal dopaminergic neurons in PD. In recent years, evidence for the role of apoptotic cell death in PD arises from morphological, as well as molecular, studies in cell cultures, animal models for PD, as well as human studies on postmortem brains from PD patients. These studies indicate that apoptosis takes place in PD and that there is a proapoptotic environment in the nigrostriatal region of parkinsonian patients. It is of utmost importance to conclusively determine the mode of cell death in PD because new "antiapoptotic" compounds may offer a means of protecting neurons from cell death and of slowing the rate of neurodegeneration and disease progression.
Liu, B. and J. S. Hong (2003). "Neuroprotective effect of naloxone in inflammation-mediated dopaminergic neurodegeneration. Dissociation from the involvement of opioid receptors." Methods Mol Med 79: 43-54.
Liu, B. and J. S. Hong (2003). "Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention." J Pharmacol Exp Ther 304(1): 1-7.
Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death. Activated microglia secrete a variety of proinflammatory and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration. In this article, we summarize recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease. In addition, we also discuss novel approaches to potential therapeutic strategies.
LoPachin, R. M., C. D. Balaban, et al. (2003). "Acrylamide axonopathy revisited." Toxicol Appl Pharmacol 188(3): 135-53.
Distal swelling and eventual degeneration of axons in the CNS and PNS have been considered to be the characteristic neuropathological features of acrylamide (ACR) neuropathy. These axonopathic changes have been the basis for classifying ACR neuropathy as a central-peripheral distal axonopathy and, accordingly, research over the past 30 years has focused on the primacy of axon damage and on deciphering underlying mechanisms. However, based on accumulating evidence, we have hypothesized that nerve terminals, and not axons, are the primary site of ACR action and that compromise of corresponding function is responsible for the autonomic, sensory, and motor defects that accompany ACR intoxication (NeuroToxicology 23 (2002) 43). In this paper, we provide a review of data from a recently completed comprehensive, longitudinal silver stain study of brain and spinal cord from rats intoxicated with ACR at two different daily dosing rates, i.e., 50 mg/kg/day, ip or 21 mg/kg/day, po. Results show that, regardless of dose-rate, ACR intoxication was associated with early, progressive nerve terminal degeneration in all CNS regions and with Purkinje cell injury in cerebellum. At the lower dose-rate, initial nerve terminal argyrophilia was followed by abundant retrograde axon degeneration in white matter tracts of spinal cord, brain stem, and cerebellum. The results support and extend our nerve terminal hypothesis and suggest that Purkinje cell damage also plays a role in ACR neurotoxicity. Substantial evidence now indicates that axon degeneration is a secondary effect and is, therefore, not pathophysiologically significant. These findings have important implications for future mechanistic research, classification schemes, and assessment of neurotoxicity risk.
McNaught, K. S. and C. W. Olanow (2003). "Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson's disease." Ann Neurol 53 Suppl 3: S73-84; discussion S84-6.
The etiopathogenesis of Parkinson's disease (PD) has been elusive. Recently, several lines of evidence have converged to suggest that defects in the ubiquitin-proteasome system and proteolytic stress underlie nigral pathology in both familial and sporadic forms of the illness. In support of this concept, mutations in alpha-synuclein that cause the protein to misfold and resist proteasomal degradation cause familial PD. Similarly, mutations in two enzymes involved in the normal function of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are also associated with hereditary PD. Furthermore, structural and function defects in 26/20S proteasomes with accumulation and aggregation of potentially cytotoxic abnormal proteins have been identified in the substantia nigra pars compacta of patients with sporadic PD. Thus, a defect in protein handling appears to be a common factor in sporadic and the various familial forms of PD. This hypothesis may also account for the vulnerability of the substantia nigra pars compacta in PD, why the disorder is age related, and the nature of the Lewy body. It has also facilitated the development of experimental models that recapitulate the behavioral and pathological features of PD, and hopefully will lead to the development of novel neuroprotective therapies for the disorder.
Michaelis, M. L. (2003). "Drugs targeting Alzheimer's disease: some things old and some things new." J Pharmacol Exp Ther 304(3): 897-904.
Enormous effort is now being devoted to developing drugs that slow neurodegeneration in Alzheimer's disease (AD), although insights into AD genetics and molecular pathogenesis only arose in the last 15 years. Acetylcholinesterase inhibitors that temporarily slow loss of cognitive function remain the only approved AD drugs. Discovery of mutations in three genes leading to severe early onset AD was critical in focusing attention on the role of amyloid peptides (Abeta) in neuronal cell death, and enhanced understanding of the biology of these peptides has led to an array of mechanism-based drug discovery strategies. These include inhibitors for Abeta-generating proteases, agents that prevent or reverse Abeta oligomerization, immunotherapies to reduce Abeta in brain and plasma, and drugs to modulate cholesterol-mediated effects on Abeta transport. Strategies are also underway to minimize toxic effects of Abeta fibrils on neurons, and these include antioxidants, blockers of glutamate-mediated excitotoxicity, and modulators of inflammatory responses within the brain. Although several approaches involve new agents for recently discovered targets, many are based on new applications of existing drugs such as statins and nonsteroidal anti-inflammatory drugs. Discovery of abnormally phosphorylated tau protein in neurofibrillary tangles in AD brain has led to strategies for identifying selective inhibitors of tau kinases and central nervous system/brain-permeable drugs that help maintain microtubule integrity. Clearly, a large gap exists between our understanding of the cellular cascades targeted in drug discovery and widespread failure of the nervous system that AD represents. Nevertheless, the pace of recent research clearly supports optimism that slowing progression of AD will soon be possible.
Michikawa, M. (2003). "The role of cholesterol in pathogenesis of Alzheimer's disease: dual metabolic interaction between amyloid beta-protein and cholesterol." Mol Neurobiol 27(1): 1-12.
The implication that cholesterol plays an essential role in the pathogenesis of Alzheimer's disease (AD) is based on the 1993 finding that the presence of apolipoprotein E (apoE) allele epsilon;4 is a strong risk factor for developing AD. Since apoE is a regulator of lipid metabolism, it is reasonable to assume that lipids such as cholesterol are involved in the pathogenesis of AD. Recent epidemiological and biochemical studies have strengthened this assumption by demonstrating the association between cholesterol and AD, and by proving that the cellular cholesterol level regulates synthesis of amyloid beta-protein (Abeta). Yet several studies have demonstrated that oligomeric Abeta affects the cellular cholesterol level, which in turn has a variety of effects on AD related pathologies, including modulation of tau phosphorylation, synapse formation and maintenance of its function, and the neurodegenerative process. All these findings suggest that the involvement of cholesterol in the pathogenesis of AD is dualistic-it is involved in Abeta generation and in the amyloid cascade, leading to disruption of synaptic plasticity, promotion of tau phosphorylation, and eventual neurodegeneration. This review article describes recent findings that may lead to the development of a strategy for AD prevention by decreasing the cellular cholesterol level, and also focuses on the impact of Abeta on cholesterol metabolism in AD and mild cognitive impairment (MCI), which may result in promotion of the amyloid cascade at later stages of the AD process.
Patel, H. C., H. Boutin, et al. (2003). "Interleukin-1 in the brain: mechanisms of action in acute neurodegeneration." Ann N Y Acad Sci 992: 39-47.
Interleukin-1 (IL-1) exerts a number of diverse actions in the brain, and it is currently well accepted that it contributes to experimentally induced neurodegeneration. Much of this is based on studies using the IL-1 receptor antagonist, which inhibits cell death caused by ischemia, brain injury, or excitotoxins. Our aim is to determine how and where in the brain IL-1 acts to produce these effects. Most of the neurodegenerative effects of IL-1 are thought to be through IL-1 beta. However, we have data implicating IL-1 alpha in excitotoxic cell death. Furthermore mice lacking both IL-1 alpha and IL-1 beta show dramatically reduced ischemic cell death, whereas deletion of IL-1 alpha or IL-1 beta alone fails to modify damage. It has also been demonstrated that IL-1 exacerbates ischemic injury in mice in the absence of the type I IL-1 receptor, suggesting the existence of novel IL-1 receptors in the brain. IL-1 also dramatically exacerbates neuronal loss in response to intrastriatal administration of the excitotoxin AMPA in the rat brain, an effect accompanied by marked increases in cytokine expression in the frontoparietal cortex, which precedes subsequent cell death in this region. Intrastriatal AMPA also results in limbic seizures that are exacerbated by IL-1, and we hypothesize, therefore, that IL-1 exacerbates cell death through increased seizure activity. Therefore, IL-1 appears to induce acute neurodegeneration through a number of mechanisms.
Plant, N. J. and G. G. Gibson (2003). "Evaluation of the toxicological relevance of CYP3A4 induction." Curr Opin Drug Discov Devel 6(1): 50-6.
CYP3A4 is the most abundant cytochrome P450 in human liver, comprising approximately 30% of the total liver P450 content. This enzyme has an important role in endogenous processes, most notably steroid catabolism, and also plays a fundamental role in the metabolism of more than half of the clinically used drugs currently prescribed. The majority of CYP3A substrates are also capable of upregulating CYP3A activity, mainly through transcriptional activation. The molecular mechanisms that underlie the transcriptional activation of CYP3A4 are complex, with many steroid hormone nuclear receptors, including GR, PXR, VDR and CAR, playing a role in these mechanisms. However, the net result of transcriptional activation is an increase in the metabolism of the inducing compounds and, therefore, increased clearance. An important side effect of this transcriptional activation is that co-administered chemicals metabolized by CYP3A may also have their pharmacokinetics altered. Such changes can result in reduced clinical efficacy of drugs, resulting in poor patient response, or the development of an adverse drug response. This review will examine examples of established interactions caused through transcriptional activation of CYP3A4, and speculate on whether such effects are clinically important and should be considered during the design of treatment regimes or, alternatively, are relatively minor and cause little physiological effects.
Przedborski, S., M. Vila, et al. (2003). "Neurodegeneration: what is it and where are we?" J Clin Invest 111(1): 3-10.
Przedborski, S., H. Mitsumoto, et al. (2003). "Recent advances in amyotrophic lateral sclerosis research." Curr Neurol Neurosci Rep 3(1): 70-7.
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. Despite several genetic breakthroughs, the actual cause and mechanism of neurodegeneration in ALS remains a mystery. Nevertheless, recent scientific and clinical advances have led to the development of new therapeutic strategies for this progressive, fatal disorder. We review the progress of the most recent clinical trials in ALS, taking into account some of the hurdles encountered by these studies. We also discuss the potential role of retroviral infection as a cause or contributor to ALS, which is one of the most recent hypotheses for the pathogenesis of the disease. The genetic background of ALS is summarized and special attention is given to the newly identified ALS gene ALS2, and to those that are currently being investigated. The last part of this review is dedicated to the mutation in superoxide dismutase-1 (SOD1). The hypothesized deleterious mechanisms of mutant SOD1 are discussed, as well as the possibilities that the mutant protein activates the apoptotic cell death process and that these molecular alterations can be exploited to devise experimental neuroprotective therapies.
Racchi, M. and S. Govoni (2003). "The pharmacology of amyloid precursor protein processing." Exp Gerontol 38(1-2): 145-57.
The possibility to understand the causes and treat the symptoms of Alzheimer's disease patients is still a great challenge. The triggering events leading to the selective neurodegeneration observed in Alzheimer's brains are not completely understood. This lack of understanding of the pathophysiological processes posses an important theoretical challenge for the rational design of pharmacological intervention. The scientific community is divided over the pathogenesis of the disease which is historically divided between 'baptists' and 'tauists'. Baptists suggest that beta-amyloid, the peptide deposited in neuritic plaques, is the cause of all damages while tauists suggest that hyperphosphorylated tau, the cytoskeletal protein that forms neurofibrillary tangles, is the culprit for the disease. This review will be focused on the pharmacological modulation of the amyloid precursor protein metabolism, with the goal of reducing the formation of beta-amyloid. Over the years such an approach has led to the identification of a complex intracellular mechanism, which may be regulated by neurotransmitters and other ligands. More recently, these efforts have contributed to the characterization of the enzymes which regulate the formation of beta-amyloid.
Robinson, S. R., G. M. Bishop, et al. (2003). "Alzheimer vaccine: amyloid-beta on trial." Bioessays 25(3): 283-8.
A new therapeutic approach is being developed for the treatment of Alzheimer's disease (AD). This approach involves the deliberate induction of an autoimmune response to amyloid-beta (Abeta) peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD. If this approach is to be effective, antibodies must be produced that can selectively target the toxic forms of Abeta, while leaving the functionally-relevant forms of Abeta and its precursor protein untouched. Furthermore, an approach needs to be found that avoids provoking an acute neuroinflammatory response. The situation is made even more challenging by uncertainty regarding which isoforms of Abeta contribute to the pathogenesis of AD.
Schousboe, A. (2003). "Role of astrocytes in the maintenance and modulation of glutamatergic and GABAergic neurotransmission." Neurochem Res 28(2): 347-52.
The functional activity in the brain is primarily composed of an interplay between excitation and inhibition. In any given region the output is based upon a complex processing of incoming signals that require both excitatory and inhibitory units. Moreover, these units must be regulated and balanced such that an integrated and finely tuned response is generated. In each of these units or synapses the activity depends on biosynthesis, release, receptor interaction, and inactivation of the neurotransmitter in question; thus, it is easily understood that each of these processes needs to be highly regulated and controlled. It is interesting to note that in case of the most prevailing neurotransmitters, glutamate and GABA, which mediate excitation and inhibition, respectively, the inactivation process is primarily maintained by highly efficient, high-affinity transport systems capable of maintaining transmembrane concentration gradients of these amino acids of 10(4)-10(5)-fold. The demonstration of the presence of transporters for glutamate and GABA in both neuronal and astrocytic elements naturally raises the question of the functional importance of the astrocytes in the regulation of the level of the neurotransmitters in the synaptic cleft and hence for the activity of excitatory and inhibitory neurotransmission. Obviously, this discussion has important implications for the understanding of the role of astrocytes in disease states in which imbalances between excitation and inhibition are a triggering factor, for example, epilepsy and neurodegeneration.
Seymour, P. A., A. W. Schmidt, et al. (2003). "The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a review." CNS Drug Rev 9(1): 57-96.
Since CRH has been shown to mediate stress-induced physiological and behavioral changes, it has been hypothesized that CRH receptor antagonists may have therapeutic potential in disorders that involve excessive CRH activity. CP-154,526 and its close analog antalarmin are potent, brain-penetrable, selective nonpeptide CRH1 receptor antagonists that were discovered in an effort to develop compounds with efficacy in CNS disorders precipitated by stress. Since its discovery many investigators have used CP-154,526 as a tool to study the pharmacology of CRH and its receptors and to evaluate its therapeutic potential in a variety of CNS and peripheral disorders. Systemically-administered CP-154,526 has been demonstrated to antagonize CRH- and stress-induced neuroendocrine, neurochemical, electrophysiological, and behavioral effects. These findings support the hypothesis that CRH1 receptor antagonists may have therapeutic utility in a number of neuropsychiatric disorders. CP-154,526, as well as other CRH1 receptor antagonists that have since been discovered, have also shown activity in several preclinical models of anxiety, depression, and substance abuse, while having little effect on locomotor activity and motor function. Although these effects are on occasion inconsistent among different laboratories, clinical evaluation of CRH1 antagonists appears justified on the basis of these and clinical data implicating the involvement of CRH in several CNS disorders. The effects of CRH1 antagonists on cognition, neurodegeneration, inflammation, and the gastrointestinal system have not been as extensively characterized and additional studies will be necessary to evaluate their therapeutic potential in these areas.
Shim, H. and Z. L. Harris (2003). "Genetic defects in copper metabolism." J Nutr 133(5 Suppl 1): 1527S-31S.
Genetic defects in copper metabolism highlight the delicate balance mammalian systems have developed to maintain normal copper homeostasis. Menkes disease, the mottled mouse, the Atox-1-deficient mouse and the ctr1 knockout mouse reveal the importance of adequate copper intake during embryogenesis and early development, especially in the central nervous system. The toxicity associated with excess copper as manifest in Wilson disease, the toxic milk mouse, the LEC rat and copper toxicosis in the Bedlington terrier demonstrate the profound cellular susceptibility to copper overload, in particular, in the brain and liver. Ceruloplasmin (Cp) contains 95% of the copper found in human serum, and inherited loss of this protein results in diabetes, retinal degeneration and neurodegeneration. Despite normal copper metabolism, aceruloplasminemic patients and the Cp knockout mouse have disturbed iron homeostasis and mild hepatic copper retention. These genetic disorders of copper metabolism provide valuable insight into the mechanisms regulating copper homeostasis and models to further dissect the role of this essential metal in health and disease.
Steward, C. G. (2003). "Neurological aspects of osteopetrosis." Neuropathol Appl Neurobiol 29(2): 87-97.
The osteopetroses are caused by reduced activity of osteoclasts which results in defective remodelling of bone and increased bone density. They range from a devastating neurometabolic disease, through severe malignant infantile osteopetrosis (OP) to two more benign conditions principally affecting adults [autosomal dominant OP (ADO I and II)]. In many patients the disease is caused by defects in either the proton pump [the a3 subunit of vacuolar-type H(+)-ATPase, encoded by the gene variously termed ATP6i or TCIRG1] or the ClC-7 chloride channel (ClCN7 gene). These pumps are responsible for acidifying the bone surface beneath the osteoclast. Although generally thought of as bone diseases, the most serious consequences of the osteopetroses are seen in the nervous system. Cranial nerves, blood vessels and the spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina. Most patients with OP have some degree of optic atrophy and many children with severe forms of autosomal recessive OP are rendered blind; optic decompression is frequently attempted to prevent the latter. Auditory, facial and trigeminal nerves may also be affected, and hydrocephalus can develop. Stenosis of both arterial supply (internal carotid and vertebral arteries) and venous drainage may occur. The least understood form of the disease is neuronopathic OP [OP and infantile neuroaxonal dystrophy, MIM (Mendelian inheritance in man) 600329] which causes rapid neurodegeneration and death within the first year. Although characterized by the finding of widespread axonal spheroids and accumulation of ceroid lipofuscin, the biochemical basis of this disease remains unknown. The neurological complications of this disease and other variants are presented in the context of the latest classification of the disease.
Sugars, K. L. and D. C. Rubinsztein (2003). "Transcriptional abnormalities in Huntington disease." Trends Genet 19(5): 233-8.
Huntington disease (HD) is caused by a CAG repeat expansion that is translated into an abnormally long polyglutamine (polyQ) tract in the huntingtin protein. The precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, but alterations in gene transcription could well be involved because the activities of several nuclear proteins are compromised by the polyQ mutation. Recent microarray studies also show relevant changes in gene expression profiles in HD models, providing useful information on the potential consequences of disrupted transcriptional pathways in HD.
Szpringer, E. and K. Lutnicki (2003). "Current views on apoptosis in theory and medical practice." Pol J Vet Sci 6(1): 71-80.
Apoptosis is a kind of cell death essential for normal functioning and survival of most multicellular organisms. Apoptosis plays an important role in physiological processes and in pathophysiology of some chronic diseases, including autoimmunity, cancer, lymphoma, AIDS, neurodegeneration and others. The present paper describes the interdisciplinary pathogenesis of programmed cell death, the mechanisms inducing apoptosis and the role of apoptosis in some physiological phenomena and in medical practice.
Tatton, W. G., R. Chalmers-Redman, et al. (2003). "Apoptosis in Parkinson's disease: signals for neuronal degradation." Ann Neurol 53 Suppl 3: S61-70; discussion S70-2.
Controversy has surrounded a role for apoptosis in the loss of neurons in Parkinson's disease (PD). Although a variety of evidence has supported an apoptotic contribution to PD neuronal loss particularly in the nigra, two factors have weighed against general acceptance: (1) limitations in the use of in situ 3' end labeling techniques to demonstrate nuclear DNA cleavage; and (2) the insistence that a specific set of nuclear morphological features be present before apoptotic death could be declared. We first review the molecular events that underlie apoptotic nuclear degradation and the literature regarding the unreliability of 3' DNA end labeling as a marker of apoptotic nuclear degradation. Recent findings regarding the multiple caspase-dependent or caspase-independent signaling pathways that mediate apoptotic nuclear degradation and determine the morphological features of apoptotic nuclear degradation are presented. The evidence shows that a single nuclear morphology is not sufficient to identify apoptosis and that a cytochrome c, pro-caspase 9, and caspase 3 pathways is operative in PD nigral apoptosis. BAX-dependent increases in mitochondrial membrane permeability are responsible for the release of mitochondrial factors that signal for apoptotic degradation, and increased BAX levels have been found in a subset of PD nigral neurons. Studies using immunocytochemistry in PD postmortem nigra have begun to define the premitochondrial apoptosis signaling pathways in the disease. Two, possibly interdependent, pathways have been uncovered: (1) a p53-glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-BAX pathway; and (2) FAS receptor-FADD-caspase 8-BAX pathway. Based on the above, it seems unlikely that apoptosis does not contribute to PD neuronal loss, and the definition of the premitochondrial signaling pathways may allow for the development and testing of an apoptosis-based PD therapy.
Tsuboi, Y., Z. K. Wszolek, et al. (2003). "[Japanese contribution to the understanding of frontotemporal dementia and parkinsonism linked to chromosome 17(FTDP-17)]." No To Shinkei 55(2): 107-19.
Since the original description of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) during the Consensus Conference held in Ann Arbor, Michigan in 1996, it has become apparent that this syndrome has worldwide distribution. More than 70 families have been described in North America, Europe, Australia and Asia. The molecular genetic studies have identified 29 mutations outside and on exon 10 of tau gene. Here, we report the progress in clinical, genetic and pathological studies of FTDP-17 in Japan. There have been 15-separetely ascertained families described in Japan. These kindreds harbor following tau mutations: exon 10, exonic mutations, N 279 K, N 296 H, P 301 L and P 301 S; exon 10 5' splice-site mutations, S 305 N (-2), +11, and +12; exon 1, R 5 H mutation; exon 9, L 266 V mutation; and exon 13, R 406 W mutation. The phenotype of FTDP-17 kindreds varies significantly between families with different mutations and among the families carrying the same mutation. This variability is also seen in Japanese kindreds. Exon 10, P 301 L, +16 and N 279 K mutations are the most common but only P 301 L and N 279 K mutations have been described so far in Japan. On the other hand, R 5 H, N 296 H, +11, and +12 mutations have not been identified outside of Japan. Comparison of phenotypes of Japanese and non-Japanese families with P 301 S, P 301 L and R 406 W mutations uncovers significant differences in clinical presentations. It is difficult to compare pathology of Japanese and non-Japanese families on the basis of available medical literature but no apparent differences can be seen. Autopsies demonstrate the presence of neuronal and glial tau inclusions and ballooned neurons, frequently in the distribution seen in other sporadic tauopathies. A search for the common founder in Japanese families may be successfully performed. FTDP-17 families have been identified with increasing frequency in Japan. The discovery of tau mutations and the fact that they are responsible for the disease processes in the brain lead to the major advancement of our understanding of neurodegeneration. It is hoped that future studies of these families will also lead to finding the curative treatments for the tauopathies.
Uberti, D., G. Ferrari Toninelli, et al. (2003). "Involvement of DNA damage and repair systems in neurodegenerative process." Toxicol Lett 139(2-3): 99-105.
The study summarizes some recent data from our and other groups underlining the contribution to neurodegeneration of two transcription factors known to be involved in DNA damage sensing and repairing: the tumour suppressor gene p53 and the component of the DNA repair system MSH2. Both proteins participate in the cancer prevention machinery for the body as well as in the neurodegenerative process, suggesting that cancer and neurodegenerative disease may share common genetic risk factors for the development and progression of the disease. Here we show that, in neuronal cells, divergent cellular insults, i.e. the exposure to glutamate, beta-amyloid (Abeta) or H(2)O(2), may converge to a common pathway that initiate with elevation of p53 protein levels. We also found that in SH-SY5Y neuronal cells H(2)O(2) induced the activation of DNA repair system with the nuclear translocation of MSH2, and PCNA. Differently no changes in MSH2 and PCNA cellular distribution were found in undifferentiating SH-SY5Y cells exposed to H(2)O(2). This argues that defects in the repair of, or response to, DNA damage impact significantly on brain function.
van Beek, J., K. Elward, et al. (2003). "Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection." Ann N Y Acad Sci 992: 56-71.
The complement system is an essential effector of the humoral and cellular immunity involved in cytolysis and immune/inflammatory responses. Complement participates in host defense against pathogens by triggering the formation of the membrane attack complex. Complement opsonins (C1q, C3b, and iC3b) interact with surface complement receptors to promote phagocytosis, whereas complement anaphylatoxins C3a and C5a initiate local inflammatory responses that ultimately contribute to the protection and healing of the host. However, activation of complement to an inappropriate extent has been proposed to promote tissue injury. There is now compelling evidence that complement activation in the brain is a double-edged sword in that it can exert beneficial or detrimental effects depending on the pathophysiological context. This review focuses on the roles of the complement system in the pathogenesis of acute brain injury (cerebral ischemia and trauma) and chronic neurodegeneration (Alzheimer's disease). Because many effects of the complement appear to promote neuronal survival and tissue remodeling, directing activation of the complement system in the brain may provide a better therapeutic rationale than inhibiting it.
Wakabayashi, K. (2003). "[Neurodegenerative disorders (2), System degeneration, no. 8 in series of articles: basic knowledge of neuropathology for neurosurgeons]." No Shinkei Geka 31(2): 216-22.
Waxman, S. G. (2003). "Nitric oxide and the axonal death cascade." Ann Neurol 53(2): 150-3.
Wells, L., S. A. Whalen, et al. (2003). "O-GlcNAc: a regulatory post-translational modification." Biochem Biophys Res Commun 302(3): 435-41.
Beta-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification of nuclear and cytosolic proteins. The enzymes for its addition and removal have recently been cloned and partially characterized. While only about 80 mammalian proteins have been identified to date that carry this modification, it is clear that this represents just a small percentage of the modified proteins. O-GlcNAc has all the properties of a regulatory modification including being dynamic and inducible. The modification appears to modulate transcriptional and signal transduction events. There are also accruing data that O-GlcNAc plays a role in apoptosis and neurodegeneration. A working model is emerging that O-GlcNAc serves as a metabolic sensor that attenuates a cell's response to extracellular stimuli based on the energy state of the cell. In this review, we will focus on the enzymes that add/remove O-GlcNAc, the functional impact of O-GlcNAc modification, and the current working model for O-GlcNAc as a nutrient sensor.
Wolferstan, F. (2003). "Slow neurodegeneration and transmissible spongiform encephalopathies/prion diseases. Hypothesis: a cycle involving repeated tyrosine kinase A activation could drive the development of TSEs." Med Hypotheses 60(1): 52-64.
Neurons are specialised non-mitogenic cells. They cannot be replaced after damage, but most survive the lifetime of the individual. This is achieved by a very specialised process of repair and regeneration.During this process, a phase of degeneration in the distal end of the damaged neuron occurs in response to tyrosine kinase activation by nerve growth factor, which results in removal of neuronal detritus from within the cell membrane. As this phase is completed the activity of tyrosine kinase is modulated and the regeneration phase begins.It is postulated that normal prions play a part in the modulation of tyrosine kinase activity; that abnormal prion isoforms may be damaged in the process releasing a few fragments of prion PrP106-126 and that these stimulate release of nerve growth factor, which activates tyrosine kinase once more, setting up the vicious spiral of slow neurodegeneration found in the transmissible spongiform encephalopathies.