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1.
Huntington's disease (HD) is caused by a polyglutamine expansion in the protein huntingtin. In its terminal stage, HD is characterized by widespread neuronal death in the neocortex and the striatum. Classically, this neuronal death has been thought to underlie most of the symptoms of the disease. Accumulating evidence suggests, however, that cellular dysfunction is important in the pathogenesis of HD. We propose that specific impairment of the exocytosis and endocytosis machinery contributes to the development of HD. We also suggest that abnormal synaptic transmission underlies the early symptoms of HD and can contribute to the triggering of cell death in later stages of the disease. 相似文献
2.
An MC Zhang N Scott G Montoro D Wittkop T Mooney S Melov S Ellerby LM 《Cell Stem Cell》2012,11(2):253-263
Huntington's disease (HD) is caused by a CAG expansion in the huntingtin gene. Expansion of the polyglutamine tract in the huntingtin protein results in massive cell death in the striatum of HD patients. We report that human induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts can be corrected by the replacement of the expanded CAG repeat with a normal repeat using homologous recombination, and that the correction persists in iPSC differentiation into DARPP-32-positive neurons in vitro and in vivo. Further, correction of the HD-iPSCs normalized pathogenic HD signaling pathways (cadherin, TGF-β, BDNF, and caspase activation) and reversed disease phenotypes such as susceptibility to cell death and altered mitochondrial bioenergetics in neural stem cells. The ability to make patient-specific, genetically corrected iPSCs from HD patients will provide relevant disease models in identical genetic backgrounds and is a critical step for the eventual use of these cells in cell replacement therapy. 相似文献
3.
Huntington's disease (HD) is caused by CAG repeat expansion in exon 1 of a large gene, IT15, possessing 67 exons. Transgenic mice expressing a truncated N-terminal peptide of huntingtin with an expanded polyglutamine tract translated only from exon 1 develop symptoms similar to Huntington's disease. In the present study, a bacterial system (Escherichia coli) was used to express truncated peptides of huntingtin translated from exon 1 of the HD gene. Bacterial death was observed after the induction of peptides with expanded polyglutamine tracts, and both sodium dodecyl sulfate (SDS)-soluble peptides and insoluble aggregated material were detected by immunoblotting in the homogenates of such E. coli. E. coli death was partially reduced by the addition of dimethylsulfoxide (DMSO) or glycerol to the medium, with a consequent decrease in aggregated material and an increase in SDS-soluble peptide in the homogenate. These results suggest that DMSO and glycerol may decrease the toxicity of huntingtin with expanded polyglutamine tracts by acting as chemical chaperones. 相似文献
4.
Mastroberardino PG Iannicola C Nardacci R Bernassola F De Laurenzi V Melino G Moreno S Pavone F Oliverio S Fesus L Piacentini M 《Cell death and differentiation》2002,9(9):873-880
By crossing Huntington's disease (HD) R6/1 transgenic mice with 'tissue' transglutaminase (TG2) knock-out mice, we have demonstrated that this multifunctional enzyme plays an important role in the neuronal death characterising this disorder in vivo. In fact, a large reduction in cell death is observed in R6/1, TG2(-/-) compared with R6/1 transgenic mice. In addition, we have shown that the formation of neuronal intranuclear inclusions (NII) is potentiated in absence of the 'tissue' transglutaminase. These phenomena are paralleled by a significant improvement both in motor performances and survival of R6/1, TG2(-/-) versus R6/1 mice. Taken together these findings suggest an important role for tissue transglutaminase in the regulation of neuronal cell death occurring in Huntington's disease. 相似文献
5.
Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease 总被引:7,自引:0,他引:7
Zeron MM Hansson O Chen N Wellington CL Leavitt BR Brundin P Hayden MR Raymond LA 《Neuron》2002,33(6):849-860
Previous work suggests N-methyl-D-aspartate receptor (NMDAR) activation may be involved in degeneration of medium-sized spiny striatal neurons in Huntington's disease (HD). Here we show that these neurons are more vulnerable to NMDAR-mediated death in a YAC transgenic FVB/N mouse model of HD expressing full-length mutant huntingtin, compared with wild-type FVB/N mice. Excitotoxic death of these neurons was increased after intrastriatal injection of quinolinate in vivo, and after NMDA but not AMPA exposure in culture. NMDA-induced cell death was abolished by an NR2B subtype-specific antagonist. In contrast, NMDAR-mediated death of cerebellar granule neurons was not enhanced, consistent with cell-type and NMDAR subtype specificity. Moreover, increased NMDA-evoked current amplitude and caspase-3 activity were observed in transgenic striatal neurons. Our data support a role for NR2B-subtype NMDAR activation as a trigger for selective neuronal degeneration in HD. 相似文献
6.
Transgenic models of Huntington's disease. 总被引:3,自引:0,他引:3
K Sathasivam C Hobbs L Mangiarini A Mahal M Turmaine P Doherty S W Davies G P Bates 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》1999,354(1386):963-969
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. A mouse model of this disease has been generated by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line (R6 lines). Transgenic mice develop a progressive neurological phenotype with a movement disorder and weight loss similar to that in HD. We have previously identified neuronal inclusions in the brains of these mice that have subsequently been established as the pathological hallmark of polyglutamine disease. Inclusions are present before symptoms, which in turn occur long before any selective neuronal cell death can be identified. We have extended the search for inclusions to skeletal muscle, which, like brain, contains terminally differentiated cells. We have conducted an investigation into the skeletal muscle atrophy that occurs in the R6 lines, (i) to provide possible insights into the muscle bulk loss observed in HD patients, and (ii) to conduct a parallel analysis into the consequence of inclusion formation to that being performed in brain. The identification of inclusions in skeletal muscle might be additionally useful in monitoring the ability of drugs to prevent inclusion formation in vivo. 相似文献
7.
Huntington's disease (HD) is a genetically dominant neurodegenerative condition caused by an unique mutation in the disease gene huntingtin. Although the Huntington protein (Htt) is ubiquitously expressed, expansion of the polyglutamine tract in Htt leads to the progressive loss of specific neuronal subpopulations in HD brains. In this article, we will summarize the current understanding on mechanisms of how mutant Htt can elicit cytotoxicity, as well as how the selective sets of neuronal cell death occur in HD brains. 相似文献
8.
HD iPSC Consortium 《Cell Stem Cell》2012,11(2):264-278
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded stretch of CAG trinucleotide repeats that results in neuronal dysfunction and death. Here, The HD Consortium reports the generation and characterization of 14 induced pluripotent stem cell (iPSC) lines from HD patients and controls. Microarray profiling revealed CAG-repeat-expansion-associated gene expression patterns that distinguish patient lines from controls, and early onset versus late onset HD. Differentiated HD neural cells showed disease-associated changes in electrophysiology, metabolism, cell adhesion, and ultimately cell death for lines with both medium and longer CAG repeat expansions. The longer repeat lines were however the most vulnerable to cellular stressors and BDNF withdrawal, as assessed using a range of assays across consortium laboratories. The HD iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in HD and provides a human stem cell platform for screening new candidate therapeutics. 相似文献
9.
S W Davies M Turmaine B A Cozens A S Raza A Mahal L Mangiarini G P Bates 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》1999,354(1386):981-989
Huntington's disease (HD) is an inherited progressive neurodegenerative disease caused by the expansion of a polyglutamine repeat sequence within a novel protein. Recent work has shown that abnormal intranuclear inclusions of aggregated mutant protein within neurons is a characteristic feature shared by HD and several other diseases involving glutamine repeat expansion. This suggests that in each of the these disorders the affected nerve cells degenerate as a result of these abnormal inclusions. A transgenic mouse model of HD has been generated by introducing exon 1 of the HD gene containing a highly expanded CAG sequence into the mouse germline. These mice develop widespread neuronal intranuclear inclusions and neurodegeneration specifically within those areas of the brain known to degenerate in HD. We have investigated the sequence of pathological changes that occur after the formation of nuclear inclusions and that precede neuronal cell death in these cells. Although the relation between inclusion formation and neurodegeneration has recently been questioned, a full characterization of the pathways linking protein aggregation and cell death will resolve some of these controversies and will additionally provide new targets for potential therapies. 相似文献
10.
Animal models of Huntington's disease 总被引:3,自引:0,他引:3
Ramaswamy S McBride JL Kordower JH 《ILAR journal / National Research Council, Institute of Laboratory Animal Resources》2007,48(4):356-373
Huntington's disease (HD) is a neurological disorder caused by a genetic mutation in the IT15 gene. Progressive cell death in the striatum and cortex, and accompanying declines in cognitive, motor, and psychiatric functions, are characteristic of the disease. Animal models of HD have provided insight into disease pathology and the outcomes of therapeutic strategies. Earlier studies of HD most often used toxin-induced models to study mitochondrial impairment and excitotoxicity-induced cell death, which are both mechanisms of degeneration seen in the HD brain. These models, based on 3-nitropropionic acid and quinolinic acid, respectively, are still often used in HD studies. The discovery in 1993 of the huntingtin mutation led to the creation of newer models that incorporate a similar genetic defect. These models, which include transgenic and knock-in rodents, are more representative of the HD progression and pathology. An even more recent model that uses a viral vector to encode the gene mutation in specific areas of the brain may be useful in nonhuman primates, as it is difficult to produce genetic models in these species. This article examines the aforementioned models and describes their use in HD research, including aspects of the creation, delivery, pathology, and tested therapies for each model. 相似文献
11.
Mormone E Matarrese P Tinari A Cannella M Maglione V Farrace MG Piacentini M Frati L Malorni W Squitieri F 《Journal of neurochemistry》2006,98(4):1090-1099
In the present work, we studied the mitochondrial function and cell death pathway(s) in heterozygous and homozygous immortalized cell lines from patients with Huntington's disease (HD). Heterozygosis was characterized by specific alterations in mitochondrial membrane potential, a constitutive hyperpolarization state of mitochondria, and was correlated with an increased susceptibility to apoptosis. Lymphoblasts from homozygous patients, on the other hand, were characterized by a significant percentage of cells displaying autophagic vacuoles. These cells also demonstrated a striking attitude towards significant cannibalistic activity. Considering the pathogenic role of cell death in HD, our study provides new and useful insights into the role of mitochondrial dysfunction, i.e. hyperpolarization, in hijacking HD heterozygous cells towards apoptosis and HD homozygous cells towards a peculiar phenotype characterized by both self- and xeno-cannibalism. These events can, however, be viewed as an ultimate attempt to survive rather than a way to die. The present work underlines the possibility that HD-associated mitochondrial defects could tentatively be by-passed by the cells by activating cellular 'phagic' activities, including so-called 'mitophagy' and 'cannibalism', that only finally lead to cell death. 相似文献
12.
Andreassen OA Ferrante RJ Hughes DB Klivenyi P Dedeoglu A Ona VO Friedlander RM Beal MF 《Journal of neurochemistry》2000,75(2):847-852
Increasing evidence implicates caspase-1-mediated cell death as a major mechanism of neuronal death in neurodegenerative diseases. In the present study we investigated the role of caspase-1 in neurotoxic experimental animal models of Huntington's disease (HD) by examining whether transgenic mice expressing a caspase-1 dominant-negative mutant are resistant to malonate and 3-nitropropionic acid (3-NP) neurotoxicity. Intrastriatal injection of malonate resulted in significantly smaller striatal lesions in mutant caspase-1 mice than those observed in littermate control mice. Caspase-1 was significantly activated following malonate intrastriatal administration in control mice but significantly attenuated in mutant caspase-1 mice. Systemic 3-NP treatment induced selective striatal lesions that were significantly smaller within mutant caspase-1 mice than in littermate control mice. These results provide further evidence of a functional role for caspase-1 in both malonate- and 3-NP-mediated neurotoxin models of HD. 相似文献
13.
Bando Y Onuki R Katayama T Manabe T Kudo T Taira K Tohyama M 《Neurochemistry international》2005,46(1):11-18
Double-strand RNA dependent protein kinase (PKR) plays an important role in control of cell death. We previously reported that activation of PKR is associated with hippocampal neuronal loss in Alzheimer's disease (AD). Recent studies have reported that Parkinson's (PD) and Huntington's (HD) disease brains displayed progressive hippocampal neuronal loss in extrastriatal degeneration. However, association between PKR and hippocampal neuronal loss in PD and HD brains is not known. In this report, brain tissues from patients with PD and HD displayed strong induction of phosphorylated-PKR (p-PKR) in hippocampal neurons. Immunoblotting analysis also demonstrated that levels of nuclear p-PKR in the hippocampus affected by these diseases were increased compared with age-matched disease controls. These results suggest that a close association exists between PKR and extrastriatal degeneration in PD and HD pathology. 相似文献
14.
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. 相似文献
15.
Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia and Friedreich's ataxia 总被引:14,自引:0,他引:14
Schapira AH 《Biochimica et biophysica acta》1999,1410(2):159-170
Respiratory chain dysfunction has been identified in several neurodegenerative disorders. In Friedreich's ataxia (FA) and Huntington's disease (HD), where the respective mutations are in nuclear genes encoding non-respiratory chain mitochondrial proteins, the defects in oxidative phosphorylation are clearly secondary. In Parkinson's disease (PD) the situation is less clear, with some evidence for a primary role of mitochondrial DNA in at least a proportion of patients. The pattern of the respiratory chain defect may provide some clue to its cause; in PD there appears to be a selective complex I deficiency; in HD and FA the deficiencies are most severe in complex II/III with a less severe defect in complex IV. Aconitase activity in HD and FA is severely decreased in brain and muscle, respectively, but appears to be normal in PD brain. Free radical generation is thought to be of importance in both HD and FA, via excitotoxicity in HD and abnormal iron handling in FA. The oxidative damage observed in PD may be secondary to the mitochondrial defect. Whatever the cause(s) and sequence of events, respiratory chain deficiencies appear to play an important role in the pathogenesis of neurodegeneration. The mitochondrial abnormalities induced may converge on the function of the mitochondrion in apoptosis. This mode of cell death is thought to play an important role in neurodegenerative diseases and it is tempting to speculate that the observed mitochondrial defects in PD, HD and FA result directly in apoptotic cell death, or in the lowering of a cell's threshold to undergo apoptosis. Clarifying the role of mitochondria in pathogenesis may provide opportunities for the development of treatments designed to reverse or prevent neurodegeneration. 相似文献
16.
J H Eubanks M Altherr C Wagner-McPherson J D McPherson J J Wasmuth G A Evans 《Genomics》1992,12(3):510-516
Genes encoding G-protein-coupled receptors, including dopamine, serotonin, muscarinic cholinergic, and adrenergic receptors, play an important role in neurotransmission and may be involved in the pathophysiology of diseases such as Alzheimer's disease, Parkinson's disease, or Huntington's disease (HD). We mapped the gene encoding the D5 dopamine receptor (DRD5) to human chromosome 4p, an area implicated in HD and the Wolf-Hirschhorn syndrome, using gene-specific amplification with the polymerase chain reaction on a panel of somatic cell hybrids carrying different human chromosomes. Further localization of the DRD5 gene was carried out through the isolation and analysis of yeast artificial chromosomes, fluorescence in situ suppression hybridization to human metaphase chromosomes, and analysis of a panel of somatic cell hybrids subdividing human chromosome 4 into nine regions. The human DRD5 gene is located at 4p15.1-p15.33, centromeric to the location of the Huntington's disease locus although not in the obligate area containing the HD gene. The localization of the DRD5 gene to 4p15.1-p15.33 suggests the possibility that cis-position effects could be responsible for the altered D1-type dopamine receptor number observed in HD tissues or that the DRD5 gene could be a candidate for some of the abnormalities associated with the Wolf-Hirschhorn syndrome. 相似文献
17.
Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73 总被引:3,自引:0,他引:3
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Hoshino M Qi ML Yoshimura N Miyashita T Tagawa K Wada Y Enokido Y Marubuchi S Harjes P Arai N Oyanagi K Blandino G Sudol M Rich T Kanazawa I Wanker EE Saitoe M Okazawa H 《The Journal of cell biology》2006,172(4):589-604
18.
Subcellular Pathology of Human Neurodegenerative Disorders: Alzheimer-Type Dementia and Huntington''s Disease 总被引:1,自引:1,他引:0
A. J. Cross T. J. Crow J. M. Dawson I. N. Ferrier J. A. Johnson T. J. Peters G. P. Reynolds 《Journal of neurochemistry》1986,47(3):882-889
Activities of enzyme markers of subcellular organelles have been measured in brain tissue from subjects with Alzheimer-type dementia (ATD) and Huntington's disease (HD). Significant increases in the activity of the lysosomal enzyme beta-glucuronidase were observed in both ATD temporal cortex and HD putamen. It is suggested that beta-glucuronidase activity may be a useful biochemical indicator of cellular damage in the CNS. A significant reduction in neutral alpha-glucosidase activity was observed in ATD temporal cortex and HD putamen. This change may reflect an alteration in glycoconjugate processing and may relate to the susceptibility of neurones to the degenerative processes of ATD and HD. 相似文献
19.
Lessons from animal models of Huntington's disease 总被引:17,自引:0,他引:17
Rubinsztein DC 《Trends in genetics : TIG》2002,18(4):202-209
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product, huntingtin. Studies in mouse models and human suggest that the mutation is associated with a deleterious gain of function. There is now a wide range of mouse models for HD, providing important insights into processes associated with disease pathogenesis. These models have been complemented by studies in Drosophila and Caenorhabditis elegans that have allowed the identification of possible modifier loci through suppressor screens. 相似文献
20.
Typical Huntington's disease (HD) was studied in a 40-year-old Sudanese man from Khartoum. He had 51 CAG repeats in the Huntington's gene. It is suspected that his mother and his 16-year-old son (both deceased) were also affected. Up to now, there had only been anecdotal evidence of HD in the Sudanese. 相似文献