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Huntington's Disease Reviews: 2004

(33 References)

Agorogiannis, E. I., G. I. Agorogiannis, et al. (2004). "Protein misfolding in neurodegenerative diseases." Neuropathol Appl Neurobiol 30(3): 215-24.

            A common pathogenic mechanism shared by diverse neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease and transmissible spongiform encephalopathies, may be altered protein homeostasis leading to protein misfolding and aggregation of a wide variety of different proteins in the form of insoluble fibrils. Mutations in the genes encoding protein constituents of these aggregates have been linked to the corresponding diseases, thus a reasonable scenario of pathogenesis was based on misfolding of a neurone-specific protein that forms insoluble fibrils that subsequently kill neuronal cells. However, during the past 5 years accumulating evidence has revealed the neurotoxic role of prefibrillar intermediate forms (soluble oligomers and protofibrils) produced during fibril formation. Many think these may be the predominant neurotoxic species, whereas microscopically visible fibrillar aggregates may not be toxic. Large protein aggregates may rather be simply inactive, or even represent a protective state that sequesters and inactivates toxic oligomers and protofibrils. Further understanding of the biochemical mechanisms involved in protein misfolding and fibrillization may optimize the planning of common therapeutic approaches for neurodegenerative diseases, directed towards reversal of protein misfolding, blockade of protein oligomerization and interference with the action of toxic proteins.

 

Alberch, J., E. Perez-Navarro, et al. (2004). "Neurotrophic factors in Huntington's disease." Prog Brain Res 146: 195-229.

            Huntington's disease is a neurodegenerative disorder characterized by the selective loss of striatal neurons and, to a lesser extent, cortical neurons. The neurodegenerative process is caused by the mutation of huntingtin gene. Recent studies have established a link between mutant huntingtin, excitotoxicity and neurotrophic factors. Neurotrophic factors prevent cell death in degenerative processes but they can also enhance growth and function of neurons that are affected in Huntington's disease. The endogenous regulation of the expression of neurotrophic factors and their receptors in the striatum and its connections can be important to protect striatal cells and maintains basal ganglia connectivity. The administration of exogenous neurotrophic factors, in animal models of Huntington's disease, has been used to characterize the trophic requirements of striatal and cortical neurons. Neurotrophins, glial cell line-derived neurotrophic factor family members and ciliary neurotrophic factor have shown a potent neuroprotective effects on different neuronal populations of the striatum. Furthermore, they are also useful to maintain the integrity of the corticostriatal pathway. Thus, these neurotrophic factors may be suitable for the development of a neuroprotective therapy for neurodegenerative disorders of the basal ganglia.

 

Beal, M. F. and R. J. Ferrante (2004). "Experimental therapeutics in transgenic mouse models of Huntington's disease." Nat Rev Neurosci 5(5): 373-84.

           

Bodemer, W. and F. J. Kaup (2004). "[Comments on present-day spread and epidemiology of BSE and prion diseases]." Gesundheitswesen 66 Suppl 1: S21-5.

            Prion diseases of animals and man are neurological diseases with amyloidal deposition of the respective proteins. As to prion disease, the cellular prion protein is in its abnormal isoform(s) an essential component of prion protein aggregates found in affected tissue. In contrast to all neurodegenerative diseases like Morbus Alzheimer or Huntington's disease, prion diseases are transmissible. Therefore, prion diseases were designated Transmissible Spongiform Encephalopathies (TSE). The diseases have been well known for decades. Scrapie was first described around 1750, a BSE case was reported in the 1850-ties most likely a misdiagnosis, and in 1920/1930 the human Creutzfeldt-Jakob disease (CJD) had been described. Transmission of CJD i. e. Kuru had been suspected in the early 1950 s and was erroneously classified as slow virus disease. The CJD transmission posed a problem to humans when transplants from CJD cases were used for treatment. Fortunately, these iatrogenic transmissions remained limited. But with the advent of BSE and appearance of variant CJD cases in the UK and some places in Europe scientists suspected that transmission from cattle to man could have happened. From animal models we know of successful transmission via several routes. Species barriers do not completely prevent transmission. Rather, transmission barriers might exist controlling individual susceptibility against prions. Modes of transmission, susceptibility to transmission, identification of receptor molecules as well as molecular mechanisms of the transmission process are being investigated with great intensity. Current knowledge leads us to assume that inapparent stages of prion infection wrongly suggest a (non-existent) species barrier. This inapparent infection precedes overt disease, and, hence, most research focuses on the development of highly sensitive assay systems for detection of minute amounts of pathological prion protein in suspected cases. Inapparence also should warn us to underestimate BSE or human vCJD cases; at present, approx. 145 cases occurred in Europe and one probable case in Hong Kong (June 2003). Whether BSE had spread to other parts of the world by animal nutrition components or meat can neither be excluded nor confirmed at this time. New data on transmission and consequences of BSE for the human population are summarised in this review.

 

Boje, K. M. (2004). "Nitric oxide neurotoxicity in neurodegenerative diseases." Front Biosci 9: 763-76.

            Nitric oxide (nitrogen monoxide; NO) is a simple molecule with diverse biological functions. NO and related reactive nitrogen oxide species (RNOS) mediate intricate physiological and pathophysiological effects in the central nervous system. Depending on environmental conditions, NO and RNOS can initiate and mediate neuroprotection or neurotoxicity either exclusively or synergistically with other effectors. The focus of this review is limited to the neuroprotectant/neurotoxic role of NO in Acquired Immune Deficiency Syndrome (AIDS) Dementia Complex (aka HIV--Associated Dementia; HAD) Amyotrophic Lateral Sclerosis (aka Lou Gehrig's Disease), Alzheimer's Disease, Huntington's Disease, Multiple Sclerosis and Parkinson's Disease. This review will shed light on the question: "How important is NO in neurodegenerative diseases?"

 

Bonelli, R. M. and P. Hofmann (2004). "A review of the treatment options for Huntington's disease." Expert Opin Pharmacother 5(4): 767-76.

            Huntington's disease (HD) is an autosomal dominant, inherited, neuropsychiatric disease which gives rise to progressive motor, cognitive and behavioural symptoms. Its core pathology involves degeneration of the basal ganglia, in particular, the caudate and putamen, and is caused by a single autosomal gene coding for a mutated form of the protein, huntingtin. At the present time, the only treatment options available in HD are symptomatic. There are several substances available today for the treatment of chorea. Other neurological symptoms, such as dystonia, can be treated, but treatment is associated with a high risk of adverse events. Psychiatric symptoms, on the other hand, are often amenable to treatment and relief of these symptoms may provide significant improvement in quality of life.

 

Bonelli, R. M., G. K. Wenning, et al. (2004). "Huntington's disease: present treatments and future therapeutic modalities." Int Clin Psychopharmacol 19(2): 51-62.

            Huntington's disease (HD) is a devastating neuropsychiatric disorder for which therapeutic interventions have been rather fruitless to date, except in a slight symptomatic relief. Even the discovery of the gene related to HD in 1993 has not effectively advanced treatments. This article is essentially a review of available double-blind, placebo-controlled trials of therapy for this condition which also includes relevant open label trials. Unfortunately, HD research has tended to concentrate on the motor aspects of the disorder, whereas the major problems are behavioural (e.g. dementia, depression, psychosis), and the chorea is often least relevant in terms of management. We conclude that there is definitely poor evidence in management of HD. The analysis of the 24 best studies fails to result in a treatment recommendation of clinical relevance. Based on data of open-label studies, or even case reports, we recommend riluzole, olanzapine and amantadine for the treatment of the movement disorders associated with HD, selective serotonin reuptake inhibitors and mirtazapine for the treatment of depression, and atypical antipsychotic drugs for HD psychosis and behavioural problems. Moreover, adjuvant psychotherapy, physiotherapy and speech therapy should be applied to supply the optimal management. Finally, some cellular mechanisms are discussed in this paper because they are essential for future neuroprotective modalities, such as minocycline, unsaturated fatty acids or riluzole.

 

Browne, S. E. and M. F. Beal (2004). "The energetics of Huntington's disease." Neurochem Res 29(3): 531-46.

            Huntington's disease (HD) is a hereditary neurodegenerative disorder that gradually robs sufferers of the ability to control movements and induces psychological and cognitive impairments. This devastating, lethal disease is one of several neurological disorders caused by trinucleotide expansions in affected genes, including spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal bulbar muscular atrophy. HD symptoms are associated with region-specific neuronal loss within the central nervous system, but to date the mechanism of this selective cell death remains unknown. Strong evidence from studies in humans and animal models suggests the involvement of energy metabolism defects, which may contribute to excitotoxic processes, oxidative dmage, and altered gene regulation. The development of transgenic mouse models expressing the human HD mutation has provided novel opportunities to explore events underlying selective neuronal death in HD, which has hitherto been impossible in humans. Here we discuss how animal models are redefining the role of energy metabolism in HD etiology.

 

Chouinard, G. (2004). "New nomenclature for drug-induced movement disorders including tardive dyskinesia." J Clin Psychiatry 65 Suppl 9: 9-15.

            Psychotropic agents are increasingly being prescribed by different specialty clinicians for a variety of psychiatric illnesses, making it necessary to improve understanding of the etiology, diagnosis, and management of drug-induced movement disorders (D-IMD) across medical specialties. Early descriptions of movement disorders were based on identifiable disease states such as parkinsonism, dystonia deformans, and Huntington's chorea, which introduced complicated and often overlapping nomenclature. This has hindered communication about, description of, and diagnosis of these drug-induced disorders. Research criteria for tardive dyskinesia, a specific, purposeless, involuntary, hyperkinetic, potentially persistent D-IMD, have varied, with relatively few data-driven conclusions available to support clinical decision-making. The differences in research criteria among published reports on rates of tardive dyskinesia with atypical antipsychotics make it difficult to find meaningful comparisons and conclusions between atypicals. A novel system for classifying D-IMD according to whether they are reversible or persistent, hypokinetic or hyperkinetic, and dystonic or nondystonic is proposed. This new classification system will provide clinicians and researchers across specialties a more precise language, which will hopefully improve the diagnosis of and research criteria for D-IMD.

 

Costa Lima, M. A. and M. M. Pimentel (2004). "Dynamic mutation and human disorders: the spinocerebellar ataxias (review)." Int J Mol Med 13(2): 299-302.

            A completely new mutational event associated with human diseases - the dynamic mutation - was discovered in the last decade. The molecular mechanism underlying dynamic mutation involves the expansion and intergenerational instability of a tandem-arrayed nucleotide sequence that acquire a pathological size, despite its polymorphic occurrence in normal individuals. To date, at least fourteen neurological disorders are associated with this phenomenon, including Huntington's disease (HD), dentatorubral and palidoluysian atrophy (DRPLA), spinobulbar and muscular atrophy (SBMA), myotonic dystrophy (DM), fragile X syndrome, FRAXE mental retardation and spinocerebellar ataxias (SCA) types 1-3, 6-8, 12 and 17. The spinocerebellar ataxias comprise a heterogeneous group of severe neurodegenerative-late onset disorders characterized by loss of balance and coordination. Most of the spinocerebellar ataxias exhibit an autosomal dominant pattern of inheritance and are promoted by the intergenerational expansion of a trinucleotide repeat (CAG)n inside the coding region of the respective gene. The expanded segment is translated into an abnormal polyglutamine tract in the protein, leading to the formation of nuclear aggregates that have been considered the basis of the pathogenesis in most of SCA types. One striking characteristic of these diseases is that the gene is expressed throughout the brain and also in other tissues but no pathological consequences are observed, despite the specific cellular degeneration. The characterization of the mutational event has led to the development of specific and sensitive molecular tests for direct DNA analysis, which allow confirmation of clinical diagnostic and an adequate therapeutic indication as well as genetic counseling.

 

Craft, S. and G. S. Watson (2004). "Insulin and neurodegenerative disease: shared and specific mechanisms." Lancet Neurol 3(3): 169-78.

            Insulin has functions in the brain and dysregulation of these functions may contribute to the expression of late-life neurodegenerative disease. We provide a brief summary of research on the influence of insulin on normal brain function. We then review evidence that perturbation of this role may contribute to the symptoms and pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. We conclude by considering whether insulin dysregulation contributes to neurodegenerative disorders through disease-specific or general mechanisms.

 

Dobson, J. (2004). "Magnetic iron compounds in neurological disorders." Ann N Y Acad Sci 1012: 183-92.

            Although iron plays an important role in many aspects of human neurophysiology, it also can be toxic under certain circumstances. Anomalous amounts of iron are known to be associated with most types of neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. To date, little is known about the specific iron compounds present in this tissue and there is recent evidence to suggest that some forms are magnetic. This raises important questions with regard to the role of magnetic iron compounds in disease initiation and progression and, indeed, the origin of these compounds. This paper reviews recent work on the identification and analysis of magnetic iron compounds associated with neurological disorders.

 

Ekshyyan, O. and T. Y. Aw (2004). "Apoptosis in acute and chronic neurological disorders." Front Biosci 9: 1567-76.

            Programmed cell death or apoptosis is a physiologically important process in neurogenesis wherein approximately 50% of the neurons apoptose during maturation of the nervous system. However, premature apoptosis and/or aberrations in apoptosis control contribute to the pathogenesis of a variety of neurological disorders including acute brain injury such as trauma, spinal cord injury, ischemic stroke and ischemia/reperfusion as well as chronic disease states such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, spinal muscular atrophy, and diabetic neuropathy. The current review will focus on two major topics, namely, the general concepts of our current understanding of the apoptosis death machinery, its mediators and regulation, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. This knowledge of apoptosis mechanisms will underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.

 

Emerich, D. F. (2004). "Sertoli cell grafts for Huntington's disease. An opinion." Neurotox Res 5(8): 567.

            The role of inflammation in CNS diseases is controversial, but growing evidence suggests that anti-inflammatory agents can minimize and/or prevent neural degeneration and its associated behavioral consequences. Sertoli cells can be grafted into the CNS to locally deliver molecules with known trophic and anti-inflammatory effects on the surrounding tissue. When Sertoli cells are grafted into the 3-nitropropionic acid (3-NP) model of Huntington's disease the protective effects are quite similar to those obtained using systemic treatments with NSAIDS (Salzberg-Benhouse et al., J. Pharmacol. Exp. Ther. 306:218-228, 2003). While these data alone do not provide unequivocal support for the notion that Sertoli cell grafts exert their beneficial effects via modulating local inflammation, they do provide an interesting convergence between data sets. The benefits of Sertoli cell grafts should be more thoroughly examined in animal models of inflammation.

 

Hannan, A. J. (2004). "Huntington's disease: which drugs might help patients?" IDrugs 7(4): 351-8.

            Huntington's disease (HD) is a fatal, genetically based brain disorder in which there is progressive neurodegeneration leading to motor, cognitive and psychiatric symptoms. The trinucleotide repeat mutation involved is common to many other brain diseases, and may therefore involve similar mechanisms of pathogenesis. We are beginning to understand how a CAG repeat expansion, encoding an expanded polyglutamine tract, induces progressive deficits in intra- and inter-cellular signaling, and subsequent disease symptoms. This review focuses on our current knowledge of molecular mechanisms of pathogenesis in HD and the use of this information to identify potential therapeutic targets and screen drugs in various transgenic models.

 

Harrower, T. P. and R. A. Barker (2004). "The emerging technologies of neural xenografting and stem cell transplantation for treating neurodegenerative disorders." Drugs Today (Barc) 40(2): 171-89.

            Neural transplantation has normally been considered in the context of the neurodegenerative disorders, Parkinson's and Huntington's disease, which are characterized pathologically by the predominant loss of specific cells in the basal ganglia. This approach has now emerged from the experimental arena into the level of clinical trial, at least with respect to fetal human allografts. However the ethical and practical problems with using such tissue has led to the search for alternative sources of cells of which two of the most promising are cells from another species, such as the pig (xenografts), and stem cells. Neural transplantation using cells derived from the developing pig brain offers many advantages. Firstly, time-mated litters will overcome the issue of donor tissue supply. Secondly, advances in genetic technology have led to the development of pigs which have a reduced rejection potential. Thirdly, xenografted neural fiber outgrowth may be superior to that from neural grafts derived from the same species (allografts) which may increase the potential for circuit reconstruction. Disadvantages with this tissue source include concerns about transmission of zoonotic infections and the immunological rejection of the xenograft. Stem cells are defined as cells capable of division (self-renewal) and differentiation into a range of different cell types (differentiation). A variety of such cells exist including embryonic stem cells, neural stem cells derived from the developing fetal brain (neural progenitor cells), adult neural stem cells and adult stem cells originating from outside of the central nervous system. Each of these different types of stem cell have their own unique benefits but also disadvantages, and access to each type is constrained by a number of limiting factors. All of this means that the translation of these cell therapies into practice is not straightforward and must be done at a pace dictated by laboratory-based research rather than corporate share price.

 

Jayakar, S. S. and M. Dikshit (2004). "AMPA receptor regulation mechanisms: future target for safer neuroprotective drugs." Int J Neurosci 114(6): 695-734.

            The post-synaptic AMPA receptors play an important role in mediating fast excitatory transmission in the mammalian brain. Over-activated AMPA receptors induce excitotoxicity, implicated in a number of Chronic neurodegenerative disorders such as Parkinson's disease, Huntington's disease, and AIDS encephalitis. AMPA receptor antagonists offer protection against neurodegeneration in the experimental models even if they are given 24 h after the injury. Because AMPA receptors seem to be involved in the neurodegenerative diseases, modulating the activity of the AMPA receptors could be an attractive approach to reduce or prevent excitotoxicity. Studies conducted recently have exhibited a number of new mechanisms for AMPA receptor regulation. Modulations of these were found to have protective implications. AMPA receptor depolarization and desensitization are protective to the neurons. Receptor desensitization depends on the receptor subunit composition. The R/G editing site and the flip/flop cassettes in AMPA receptor subunits contribute to a great extent in receptor desensitization and recovery rates. Molecules that could quicken receptor desensitization or delay recovery could be of use. AMPA receptors limit neuronal entry of Ca2+ ions by regulating Ca2+-permeability. Ca2+-permeable receptor channels are made up of GluR1, GluR3, or GluR4 subunits, whereas presence of the GluR2 subunit restricts Ca2+ entry and renders the receptor Ca2+-impermeable. GluR2 levels, however, experience a fall after neuronal insult rendering the AMPA receptors Ca2+-permeable, thus factors that could interfere with this event might prove to be very beneficial against excitotoxicity. AMPA receptor clusters are stabilized by PSD-95, which requires palmitoylation at two sites. Targeting palmitoylation of the PSD-95 can also be a useful approach to disperse AMPA clusters at the synapse. In the perisynaptic region, mGluRs are present a little away from the synapse and are among the glutamate transporters, which require high-frequency firing for activation. On activation they might enhance the activity of NMDA receptors at the synapse to increase the levels of AMPA receptors. AMPA receptors surfaced at this juncture can contribute to heavy Ca2+ influx. Thus, blocking this pathway could be of considerable importance in preventing the excitotoxicity. A number of proteins such as the GRIP, PICK, and NSF also modulate the functions of AMPA receptors. Polyamines also block Ca2+ permeable AMPA receptors and thus are protective. NO and cGMP also play an important role in negatively regulating AMPA receptors and thus could offer protection. Modulation of AMPA receptor by different mechanisms has been discussed in the present review to implicate importance of these targets/pathways for safer and future neuroprotective drugs.

 

Kent, A. (2004). "Huntington's disease." Nurs Stand 18(32): 45-51; quiz 52-3.

            Huntington's disease is a complex degenerative disorder that affects the central nervous system. Although it is a rare condition, nurses are ideally placed to assess and manage patients with the disease, while also providing information and support to family members. This article discusses the cause and symptoms, explains the method of diagnosis and outlines the role of the nurse in caring for patients with Huntington's disease.

 

Khidiiatova, I. M. and E. K. Khusnutdinova (2004). "[Genomic structure and DNA diagnosis of hereditary monogenic diseases in the Volga-Ural region]." Mol Biol (Mosk) 38(1): 139-49.

            The review considers the main results of molecular analysis of the genes responsible for cystic fibrosis, phenylketonuria, Wilson-Konovalov disease, Duchenne-Becker progressive muscular dystrophy, myotonic dystrophy, Huntington's disease, and nonsyndromic hereditary hypoacusis in populations of the Volga-Ural region. The results were obtained in the past ten years within the framework of the Russian program Human Genome. The mutation spectra and frequencies of these genes were characterized in the major ethnic groups (Bashkirs, Tatars, Russians) of Bashkortostan. Several diseases were associated with particular alleles or haplotypes of polymorphic loci of relevant genes. The results were used to develop DNA diagnostic procedures optimal for the region and to establish the origin of the mutations involved.

 

Lee, W. T. and C. Chang (2004). "Magnetic resonance imaging and spectroscopy in assessing 3-nitropropionic acid-induced brain lesions: an animal model of Huntington's disease." Prog Neurobiol 72(2): 87-110.

            Huntington's disease (HD) is an inherited neurodegenerative disease, in which there is progressive motor and cognitive deterioration, and for which the pathogenesis of neuronal death remains controversial. Mitochondrial toxins like 3-nitropropionic acid (3-NP) and malonate, functioning as the inhibitors of the complex II of mitochondrial respiratory chain, have been found to effectively induce specific behavioral changes and selective striatal lesions in rats and non-human primates mimicking those in HD. Furthermore, several kinds of transgenic mouse models of HD have been recently developed, and used in the development and assessment of novel treatments for HD. In the past, most studies evaluating the animal models for HD were based on histological changes or in vitro neuronal cultures. With the emergence of advanced magnetic resonance technologies, non-invasive magnetic resonance imaging (MRI) and spectroscopy provide more detail of cerebral alterations, including the changes of cerebral structure, function and metabolites. These studies support the hypothesis that mitochondrial dysfunction with increased excitation of N-methyl-D-aspartate (NMDA) receptors can replicate the neurobehavioral changes, selective brain injury and neurochemical alterations in HD. The present review focuses on our work as well as that of others regarding 3-NP-induced neurotoxicity and other animal models of HD. Using both conventional and advanced MRI and spectroscopy, we summarize the pathogenesis and possible therapeutic strategies in chemical and transgenic models of HD. The results show magnetic resonance techniques to be powerful techniques in the evaluation of pathogenesis and therapeutic intervention for both chemical and transgenic models of HD.

 

Li, S. H. and X. J. Li (2004). "Huntingtin-protein interactions and the pathogenesis of Huntington's disease." Trends Genet 20(3): 146-54.

            At least nine inherited neurodegenerative diseases share a polyglutamine expansion in their respective disease proteins. These diseases show distinct neuropathological changes, suggesting that protein environment and protein-protein interactions play an important role in the specific neuropathology. A gain of toxic function as a result of an expanded polyglutamine tract can cause the protein huntingtin to interact abnormally with a variety of proteins, resulting in the complex of neuropathological changes seen in Huntington's disease. Recent studies have identified several huntingtin-interacting proteins that might be associated with the normal function of huntingtin and/or involved in the pathology of Huntington's disease. In this article, we focus on the potential roles of huntingtin-protein interactions in the pathogenesis of Huntington's disease.

 

Marsh, J. L. and L. M. Thompson (2004). "Can flies help humans treat neurodegenerative diseases?" Bioessays 26(5): 485-96.

            Neurodegenerative diseases are becoming increasingly common as life expectancy increases. Recent years have seen tremendous progress in the identification of genes that cause these diseases. While mutations have been found and cellular processes defined that are altered in the disease state, the identification of treatments and cures has proven more elusive. The process of finding drugs and therapies to treat human diseases can be slow, expensive and frustrating. Can model organisms such as Drosophila speed the process of finding cures and treatments for human neurodegenerative diseases? We pose three questions, (1) can one mimic the essential features of human diseases in an organism like Drosophila, (2) can one cure a model organisms of human disease and (3) will these efforts accelerate the identification of useful therapies for testing in mice and ultimately humans? Here we focus on the use of Drosophila to identify potential treatments for neurodegenerative diseases such as Huntington's and we discuss how well these therapies translate into mammalian systems.

 

Mattson, M. P. (2004). "Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders." Ann N Y Acad Sci 1012: 37-50.

            Membrane lipid peroxidation and oxidative modification of various membrane and associated proteins (e.g., receptors, ion transporters and channels, and signal transduction and cytoskeletal proteins) occur in a range of neurodegenerative disorders. This membrane-associated oxidative stress (MAOS) is promoted by redox-active metals, most notably iron and copper. The mechanisms whereby different genetic and environmental factors initiate MAOS in specific neurological disorders are being elucidated. In Alzheimer's disease (AD), the amyloid beta-peptide generates reactive oxygen species and induces MAOS, resulting in disruption of cellular calcium homeostasis. In Parkinson's disease (PD), mitochondrial toxins and perturbed ubiquitin-dependent proteolysis may impair ATP production and increase oxyradical production and MAOS. The inheritance of polyglutamine-expanded huntingtin may promote neuronal degeneration in Huntington's disease (HD), in part, by increasing MAOS. Increased MAOS occurs in amyotrophic lateral sclerosis (ALS) as the result of genetic abnormalities (e.g., Cu/Zn-superoxide dismutase mutations) or exposure to environmental toxins. Levels of iron are increased in vulnerable neuronal populations in AD and PD, and dietary and pharmacological manipulations of iron and copper modify the course of the disease in mouse models of AD and PD in ways that suggest a role for these metals in disease pathogenesis. An increasing number of pharmacological and dietary interventions are being identified that can suppress MAOS and neuronal damage and improve functional outcome in animal models of AD, PD, HD, and ALS. Novel preventative and therapeutic approaches for neurodegenerative disorders are emerging from basic research on the molecular and cellular actions of metals and MAOS in neural cells.

 

Montine, K. S., J. F. Quinn, et al. (2004). "Isoprostanes and related products of lipid peroxidation in neurodegenerative diseases." Chem Phys Lipids 128(1-2): 117-24.

            Lipid peroxidation is a major outcome of free radical-mediated injury to brain, where it directly damages membranes and generates a number of oxidized products. Some of the chemically and metabolically stable oxidation products are useful in vivo biomarkers of lipid peroxidation. These include the isoprostanes (IsoPs) and isofurans (IsoFs), derived from arachidonic acid (AA), and neuroprostanes (NeuroPs), derived from docosahexaenoic acid (DHA). We have shown increased levels of IsoPs, NeuroPs, and IsoFs in diseased regions of brain from patients who died from advanced Alzheimer's disease (AD) or Parkinson's disease (PD). Increased cerebrospinal fluid (CSF) levels of IsoPs are present in patients with AD or Huntington's disease (HD) early in the course of their illness, and CSF IsoPs may improve the laboratory diagnostic accuracy for AD. In contrast, quantification of IsoPs in plasma and urine of AD patients has yielded inconsistent results. These results indicate that brain lipid peroxidation is a potential therapeutic target early in the course of AD and HD, that CSF IsoPs may aid in the assessment of anti-oxidant experimental therapeutics and laboratory diagnosis of AD.

 

Moos, T. and E. H. Morgan (2004). "The metabolism of neuronal iron and its pathogenic role in neurological disease: review." Ann N Y Acad Sci 1012: 14-26.

            Neurons need iron, which is reflected in their expression of the transferrin receptor. The concurrent expression of the ferrous iron transporter, divalent metal transporter I (DMT1), in neurons suggests that the internalization of transferrin is followed by detachment of iron within recycling endosomes and transport into the cytosol via DMT1. To enable DMT1-mediated export of iron from the endosome to the cytosol, ferric iron must be reduced to its ferrous form, which could be mediated by a ferric reductase. The presence of nontransferrin-bound iron in brain extracellular fluids suggests that neurons can also take up iron in a transferrin-free form. Neurons are thought to be devoid of ferritin in many brain regions in which there is an association between iron accumulation and cellular damage, for example, neurons of the substantia nigra pars compacta. The general lack of ferritin together with the prevailing expression of the transferrin receptor indicates that iron acquired by activity of transferrin receptors is directed toward immediate use in relevant metabolic processes, is exported, or is incorporated into complexes other than ferritin. Iron has long been considered to play a significant role in exacerbating degradation processes in brain tissue subjected to acute damage and neurodegenerative disorders. In brain ischemia, the damaging role of iron may depend on the inhibition of detoxifying enzymes responsible for catalyzing the oxidation of ferrous iron. Brain ischemia may also lead to an increase in iron supply to neurons as transferrin receptor expression by brain capillary endothelial cells is increased. Pharmacological blockage of the transferrin receptor/DMT1-mediated uptake could be a target to prevent further iron uptake. In chronic neurodegenerative settings, a deleterious role of iron is suggested since cases of Alzheimer's disease, Parkinson's disease, and Huntington's disease have a significantly higher accumulation of iron in affected regions. Dopaminergic neurons are rich in neuromelanin, shown to be more redox-active in Parkinson's disease cases. Iron-containing inflammatory cells may, however, account for the main portion of iron present in neurodegenerative disorders. More knowledge about iron metabolism in normal and diseased neurons is warranted as this may identify pharmaceutical targets to improve neuronal iron management.

 

Newman, M. B., C. D. Davis, et al. (2004). "Transplantation of human umbilical cord blood cells in the repair of CNS diseases." Expert Opin Biol Ther 4(2): 121-30.

            Cell transplantation therapies have been used to treat certain neurodegenerative diseases such as Parkinson's and Huntington's disease. However, ethical concerns over the use of fetal tissues, and the inherent complexities of standardising the procurement, processing and transplantation methods of this tissue, have prompted the search for a source of cells that have less ethical stigmatisations, are readily available and can be easily standardised. Several sources of human cells that meet these principles have been under investigation. Cells from human umbilical cord blood (HUCB) are one source that is consistent with these principles; therefore, they have become of great interest in the field of cellular repair/replacement for the treatment of CNS diseases and injury. This review will focus on the advantages of HUCB cells as a source for cellular transplantation therapies, recent studies that have examined the potential of these cells in vitro to be directed towards neural phenotypes, and in vivo studies that have investigated the functional recovery of animals in a number of models of CNS injury and disease following administration of HUCB cells.

 

Nikolaus, S., M. Beu, et al. (2004). "The contribution of small animal positron emission tomography to the neurosciences--a critical evaluation." Rev Neurosci 15(2): 131-56.

            This article presents an overview of those animal studies which so far have been performed with dedicated small animal positron emission tomographs in the field of the neurosciences. In vivo investigations focus on energy metabolism, perfusion and receptor/transporter binding in rat models of reinforcement, learning and memory, traumatic brain injury, epilepsy, depression, cardiovascular diseases--such as ischemia and focal stroke--and neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. In the majority of studies, important novel aspects arise from the fact that the investigators made use of an option inherent to in vivo studies, namely to conduct longitudinal investigations on the same animals. Relevant findings pertain to the relationship of brain metabolism/perfusion and the cholinergic system, the regulation state of dopamine receptors upon cocaine administration and withdrawal, the regulation state of dopamine receptors and transporters in animal models of Parkinson's and Huntington's disease, and potential treatments of progressive dopaminergic depletion with adenoviral vectors, embryonic grafts, stem cells and nerve growth factors.

 

Peschanski, M., A. C. Bachoud-Levi, et al. (2004). "Integrating fetal neural transplants into a therapeutic strategy: the example of Huntington's disease." Brain 127(Pt 6): 1219-28.

            Fetal neural transplants have become clinically relevant over the past 15 years for two major neurodegenerative diseases, namely Parkinson's disease and Huntington's disease. It is therefore timely to consider how this neurosurgical procedure can integrate the therapeutic armamentarium, what can be expected of it, and what cannot. We use here the example of Huntington's disease to show what fetal neural transplants may uniquely offer for that disease. Up to very recent times, Huntington's disease has been one special example of those neurodegenerative diseases against which neurologists feel totally helpless. This has all changed today and, although results are essentially still to come, one can foresee the mobilization of very large scientific and medical forces against this disease, with definite steps forward in terms of physiopathology and a better view of the therapeutic challenges. While defining the role that fetal neural transplantation may play in meeting these challenges, we also try to show rationales and developments for all types of treatments attempted or suggested so far, as well as their limits and, when relevant, informative failures. The date of writing this review needs to be noted, because the rapid accumulation of data on molecular mechanisms of Huntington's disease pathogenesis and the increasing numbers of clinical trials do not allow much time for the ink of a review to dry.

 

Richardson, D. R. (2004). "Novel chelators for central nervous system disorders that involve alterations in the metabolism of iron and other metal ions." Ann N Y Acad Sci 1012: 326-41.

            Recent evidence suggests that iron (Fe) and other metals play a role in a number of neurodegenerative diseases including Friedreich's ataxia, Alzheimer's disease, Huntington's disease, and Parkinson's disease. In this review, the role of Fe and other metals in the pathology of these conditions is assessed and the potential of Fe chelators for treatment is discussed. Lipophilic chelators have been designed that may be capable of crossing the blood-brain barrier, a property lacking in desferrioxamine (DFO), a chelator in widespread clinical use. A far less commonly used chelator, clioquinol, has already shown activity in vivo in animal models and also in Alzheimer's disease patients. Considering that there is no effective treatment for many neurological diseases, the therapeutic use of lipophilic Fe chelators remains a potential strategy that requires investigation. In particular, we discuss the development of several series of aroylhydrazone chelators that could have high potential in the treatment of these diseases.

 

Trzesniewska, K., M. Brzyska, et al. (2004). "Neurodegenerative aspects of protein aggregation." Acta Neurobiol Exp (Wars) 64(1): 41-52.

            Protein aggregation and amyloid fibril deposits are characteristic features of more than twenty pathologic conditions characterized by plaque deposition in the central nervous system. Recent studies point out relationships between protein misfolding and numerous serious diseases. Despite different origins (sporadic, familial or transmissible), they are sometimes called conformational diseases to emphasize aberrant conformations as the putative cause of deposits that precede or accompany the clinical manifestation of the disease. Neurological disorders such as Alzheimer's disease (AD), Prion disorders (PrD), Parkinson's disease (PD), and Huntington's disease (HD) are the most typical examples of protein-based dementias, characterized by protein conformational transitions (alpha-helix/random coil to beta-sheet) that cause aggregation followed by fibrillization. Although it is very tempting to postulate a common mechanism of toxicity based on conformational and structural analogies, it should be noted that the factors responsible for conformational transition, oligomerization, aggregation, and plaque formation, are still subject of speculation and additional data is required to test the amyloid fibril hypothesis.

 

van Dellen, A. and A. J. Hannan (2004). "Genetic and environmental factors in the pathogenesis of Huntington's disease." Neurogenetics 5(1): 9-17.

            Huntington's disease is a fatal inherited disorder in which there is progressive neurodegeneration in specific brain areas, mainly the striatum and cerebral cortex, producing motor, cognitive, and psychiatric symptoms. The trinucleotide repeat mutation involved is common to many other brain diseases, which may therefore involve similar mechanisms of pathogenesis. We are beginning to understand how a CAG trinucleotide repeat expansion in the disease gene, encoding an expanded polyglutamine tract, induces neuronal dysfunction and symptomatology in Huntington's disease. Recent evidence that environmental factors modify the onset and progression of neurodegeneration has shed new light on Huntington's disease and other devastating brain diseases. This review focuses on genetic mediators, environmental modulators, and associated gene-environment interactions in the pathogenesis of Huntington's disease.

 

Zeman, A., J. Stone, et al. (2004). "Spinocerebellar ataxia type 8 in Scotland: genetic and clinical features in seven unrelated cases and a review of published reports." J Neurol Neurosurg Psychiatry 75(3): 459-65.

            OBJECTIVES: To establish whether the DNA expansion linked to spinocerebellar ataxia type 8 (SCA 8) is associated with ataxia in Scotland; to clarify the range of associated clinical phenotypes; and to compare the findings with previous reports. METHODS: DNA was screened from 1190 anonymised controls, 137 subjects who had tested negative for Huntington's disease, 176 with schizophrenia, and 173 with undiagnosed ataxia. Five unrelated ataxic patients with the SCA 8 expansion and a sixth identified subsequently had clinical and psychometric assessment; the clinical features were available in a seventh. A systematic search for other reports of SCA 8 was undertaken. RESULTS: Over 98% of SCA 8 CTA/CTG repeat lengths fell between 14 and 40. Repeat lengths over 91 were observed in three healthy controls (0.12%), two patients with suspected Huntington's disease (0.73%), and six ataxic subjects (1.74%; p<0.0005 v healthy controls). Repeat lengths over 100 occurred in five ataxic subjects but in only one control. All seven symptomatic subjects with the SCA 8 expansion had a cerebellar syndrome; four had upper motor neurone signs; and 5/6 assessed had cognitive complaints. There was personality change in two and mood disturbance in three. In published reports, SCA 8 repeat lengths over 91 occurred in approximately 0.5% of the healthy population but were over-represented among ataxic patients (3.4%; p<0.0001). The predominant clinical phenotype was cerebellar, with pyramidal signs in 50%, and neuropsychiatric features in some cases. CONCLUSIONS: SCA 8 expansion is a risk factor for a cerebellar syndrome, often associated with upper motor neurone and neuropsychiatric features. The expansion occurs unexpectedly often in the general population.

 

Zhu, B. T. (2004). "CNS dopamine oxidation and catechol-O-methyltransferase: importance in the etiology, pharmacotherapy, and dietary prevention of Parkinson's disease." Int J Mol Med 13(3): 343-53.

            In this article, a particular emphasis has been placed on the conceptual development and understanding of the unique pathogenic changes that are indigenous to the striatal dopaminergic neurons as an important etiological factor in human Parkinson's disease (PD) as well as on the understanding of their clinical implications. Specifically, I have discussed the etiological roles of central nervous system dopamine oxidation in PD, along with a critical review of the available evidence in support of the proposed hypotheses. The chemically-reactive dopamine quinone/semiquinone intermediates are known to be highly neurotoxic and potentially genotoxic. There is considerable evidence for the suggestion that the long-term use of levodopa accelerates the progression of PD. In comparison, centrally-acting non-catechol dopamine receptor agonists would be an excellent alternative to levodopa for the treatment of PD (particularly for late-stage PD) because these agents would not undergo redox cycling to cause oxidative neuronal damage. Catechol-O-methyltransferase (COMT)-mediated methylation metabolism of catecholamine neurotransmitters is a crucial first-line detoxification pathway, and its role in the causation and prevention of PD is also discussed. On the basis of the modulation of COMT-mediated methylation of catecholamines, it is mechanistically explained that hyperhomocysteinemia would be a pathogenic factor in PD whereas vitamins B6, B12, and folate would be a protective factor. Lastly, according to the mechanistic understanding developed here, a novel dietary strategy is proposed that is specifically tailored toward lowering the risk of human PD, which includes eating a nutritionally-balanced diet that contains adequate (but not excessive) amounts of fruits and vegetables, along with adequate dietary supplementation of S-adenosyl-L-methionine, vitamins C, B6, B12, and folate. It is believed that these conceptual developments would also aid in our better understanding of other age-related neurodegenerative disorders, such as Alzheimer's and Huntington's diseases.

           

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