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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder similar to Huntington's disease, with clinical manifestations including chorea, incoordination, ataxia, and dementia. It is caused by an expansion of a CAG trinucleotide repeat encoding polyglutamine in the atrophin-1 gene. Both patients and DRPLA transgenic mice have nuclear accumulation of atrophin-1, especially an approximately 120-kDa fragment, which appears to represent a cleavage product. We now show that this is an N-terminal fragment that does not correspond to the previously described caspase-3 fragment, or any other known caspase cleavage product. The atrophin-1 sequence contains a putative nuclear localization signal in the N terminus of the protein and a putative nuclear export signal in the C terminus. We have tested the hypothesis that endogenous localization signals are functional in atrophin-1, and that nuclear localization and proteolytic cleavage contribute to atrophin-1 cell toxicity. In transient cell transfection experiments using a neuroblastoma cell line, full-length atrophin-1 with 26 (normal) or 65 (expanded) glutamines localized to both nucleus and cytoplasm, with no significant difference in toxicity between the normal and mutant proteins. A construct with 65 glutamine repeats encoding an N-terminal fragment (which removes an NES) of atrophin-1 similar in size to the truncation product in DRPLA patient tissue, showed increased nuclear labeling, and an increase in cellular toxicity, compared with a similar fragment with 26 glutamines. Full-length atrophin-1 with 65 polyglutamine repeats and mutations inactivating the NES also yielded increased nuclear localization and increased toxicity. These data suggest that truncation enhances cellular toxicity of the mutant protein, and that the NES is a relevant region deleted during truncation. Furthermore, mutating the NLS in the truncated protein shifted atrophin-1 more to the cytoplasm and eliminated the increased toxicity, consistent with the idea that nuclear localization enhances toxicity. In none of the experiments were inclusions visible in the nucleus or cytoplasm suggesting that inclusion formation is unrelated to cell death. These data indicate that truncation of atrophin-1 may alter its ability to shuttle between the nucleus and cytoplasm, leading to abnormal nuclear interactions and cell toxicity.
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PMID:Nuclear localization of a non-caspase truncation product of atrophin-1, with an expanded polyglutamine repeat, increases cellular toxicity. 1246 7

We describe the genetic and neurological features of toppler, a spontaneous autosomal mutation that appeared in a colony of FVB/N mice and that manifests as severe ataxia appearing at around 12 days of age, worsening with age. The lifespan of affected mice is 8-12 months, with occasional mice living longer. Both homozygous males and females are fertile, and females are able to nurture litters. Histological examination of brain revealed no striking abnormalities other than the loss of cerebellar Purkinje cells. The toppler mutation was mapped to mouse chromosome 8, and to assess whether it was novel or a recurrence of a previously described chromosome 8 mouse mutant, toppler mice were crossed with the nervous and tottering mouse mutants. These studies demonstrate that toppler is a unique mouse mutation. Purkinje cell abnormalities in toppler mice were obvious around postnatal day (P) 14, i.e., toppler Purkinje cells already exhibited abnormal morphology. Staining for calbindin, a calcium binding protein enriched in Purkinje cells, showed altered dendritic morphology. Between P14 and P30, dramatic Purkinje cell loss occurred, although there were differences in the degree of Purkinje cell loss in each lobule. At P30, the surviving Purkinje cells expressed zebrin II. From P30 through 6 months, many of the remaining Purkinje cells gradually degenerated. Purkinje cell loss was analyzed by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL), and Purkinje cells were TUNEL-positive most abundantly at P21. In addition, Bergmann glia were TUNEL positive at P21, and they expressed activated caspase-3 at earlier time points. Interestingly, despite the apparent death of some Bergmann glia, there was up-regulation of glial fibrillary acidic protein, expressed in astrocytes as well as Bergmann glia. Given the changes in both Purkinje cells and glia in toppler cerebellum, this may be a very useful model in which to investigate the developmental interaction of Purkinje cells and Bergmann glia.
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PMID:The toppler mouse: a novel mutant exhibiting loss of Purkinje cells. 1524 93

Most cerebellar granule neurons in weaver mice undergo premature apoptosis during the first 3 postnatal weeks, subsequently leading to severe ataxia. The death of these granule neurons appears to result from a point mutation in the GIRK2 gene, which encodes a G protein-activated, inwardly rectifying K+ channel protein. Although the genetic defect was identified, the molecular mechanism by which the mutant K+ channel selectively attacks granule neurons in weaver mice is unclear. Before their demise, weaver granule neurons express abnormally high levels of insulin-like growth factor (IGF) binding protein 5 (IGFBP5). IGF-I is essential for the survival of cerebellar neurons during their differentiation. Because IGFBP5 has the capacity to block IGF-I activity, we hypothesized that reduced IGF-I availability resulting from excess IGFBP5 accelerates the apoptosis of weaver granule neurons. We found that, consistently with this hypothesis, exogenous IGF-I partially protected cultured weaver granule neurons from apoptosis by activating Akt and decreasing caspase-3 activity. To determine whether IGF-I protects granule neurons in vivo, we cross-bred weaver mice with transgenic mice that overexpress IGF-I in the cerebellum. The cerebellar volume was increased in weaver mice carrying the IGF-I transgene, predominantly because of an increased number of surviving granule neurons. The presence of the IGF-I transgene resulted in improved muscle strength and a reduction in ataxia, indicating that the surviving granule neurons are functionally integrated into the cerebellar neuronal circuitry. These results confirm our previous suggestion that a lack of IGF-I activity contributes to apoptosis of weaver granule neurons in vivo and supports IGF-I's potential therapeutic use in neurodegenerative disease.
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PMID:Insulin-like growth factor-I protects granule neurons from apoptosis and improves ataxia in weaver mice. 1584 77

To investigate the mechanisms(s) of age-dependent atrophy of the cerebellum of the ataxia and male sterility (AMS) mouse at young age, the morphological changes were evaluated and the nature of neural cell death was examined. Dying Purkinje cells lacked characters of classical apoptosis except for light microscopic morphology, but their death was considered to be autonomous death triggered by the direct effect of ams mutation, because of the acute and near-complete disappearance and particular change of the cytoplasm. In contrast, in the granular layer, typical apoptotic bodies were recognized by electron microscopy, and substantial numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end-labeling (TUNEL)-positive cells and activated caspase-3-positive cells were observed. Granule cell death was considered to be target-related apoptosis induced after post-synaptic Purkinje cell death, because the age-dependent changes in TUNEL-positive cell counts followed that of Purkinje cell loss and the peak value was still noted 1 week after total loss of Purkinje cells. These results indicate that both total and partial losses of Purkinje cells and granule cells, respectively, contributed to the atrophy of the AMS cerebellum. Furthermore, different types of neuronal death were recognized; the granule cell death was apoptotic while Purkinje cell death was different from that of classical apoptosis.
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PMID:Different types of neural cell death in the cerebellum of the ataxia and male sterility (AMS) mutant mouse. 1663 62

Failure to control oxidative stress is closely related to aging and to a diverse range of human diseases. We have reported that protein kinase C gamma (PKCgamma) acts as a primary oxidative stress sensor in the lens. PKCgamma has a Zn-finger C1B stress switch domain, residues 101-150. Mutation, H101Y, in the C1B domain of PKCgamma proteins causes a failure of the PKCgamma oxidative stress response [Lin, D., Takemoto, D.J., 2005. Oxidative activation of protein kinase Cgamma through the C1 domain. Effects on gap junctions. J. Biol. Chem. 280, 13682-13693]. Some human neurodegenerative spinocerebellar ataxia type 14 are caused by mutations in the PKCgamma C1B domain. In the current study we have investigated the effects of these mutations on lens epithelial cell responses to oxidative stress. The results demonstrate that PKCgamma C1B mutants had lower basal enzyme activities and were not activated by H(2)O(2). Furthermore, the PKCgamma mutations caused a failure of endogenous wild type PKCgamma to be activated by H(2)O(2). These PKCgamma mutations abolished the effect of H(2)O(2) on phosphorylation of Cx43 and Cx50 by H(2)O(2) activation of PKCgamma. The cells with PKCgamma C1B mutations had more Cx43 and/or Cx50 gap junction plaques which were not decreased by H(2)O(2). Since open gap junctions could have a bystander effect this could cause apoptosis to occur. H(2)O(2) (100 microM, 3 h) activated a caspase-3 apoptotic pathway in the lens epithelial cells but was more severe in cells expressing PKCgamma mutations. The presence of 18alpha-glycyrrhetinic acid (AGA), an inhibitor of gap junctions, decreased Cx43 and Cx50 protein levels and gap junction plaque number. This reduction in gap junctions by AGA resulted in inhibition of H(2)O(2)-induced apoptosis. Our results demonstrate that there is a dominant negative effect of PKCgamma C1B mutations on endogenous PKCgamma which results in loss of control of gap junctions. Modeled structures suggest that the severity of C1B mutation effects may be related to the extent of loss of C1B structure. Mutations in the C1B domain of PKCgamma result in increased apoptosis in lens epithelial cells. This can be prevented by a gap junction inhibitor. Thus, propagation of apoptosis from cell-to-cell in lens epithelial cells may be through open gap junctions. The control of gap junctions requires PKCgamma.
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PMID:Protein kinase C gamma mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions. 1749 14

Mutations in the protein kinase C gamma (PKCgamma) gene cause spinocerebellar ataxia type 14 (SCA14), a heterogeneous neurodegenerative disorder. Synthetic peptides (C1B1) serve as gap junction inhibitors through activation of PKCgamma control of gap junctions. We investigated the neuroprotective potential of these peptides against SCA14 mutation-induced cell death using neuronal HT22 cells. The C1B1 synthetic peptides completely restored PKCgamma enzyme activity and subsequent control of gap junctions. PKCgamma SCA14 mutant proteins were shown to cause aggregation which initially resulted in endoplasmic reticulum (ER) stress and cell apoptosis as demonstrated by phosphorylation of PERK on Thr981, activation of caspase-12, increases in BiP/GRP78 protein levels, and consequent activation of caspase-3. Pre-incubation with C1B1 peptides completely abolished these SCA14 effects on ER stress and caspase-3 activation, suggesting that C1B1 peptides protect cells from apoptosis through inhibition of gap junctions by restoration of PKCgamma control of gap junctions, which may result in neuroprotection in SCA14.
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PMID:Protection from ataxia-linked apoptosis by gap junction inhibitors. 1782 69

Several causal missense mutations in protein kinase C gamma (gamma PKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that mutant gamma PKC found in SCA14 is susceptible to two types of aggregation, cytoplasmic dot-like and perinuclear massive aggregation, and causes cell death in Chinese hamster ovary cells. Long-term time-lapse imaging revealed that firstly accumulated dot-like aggregation of mutant gamma PKC-green fluorescent protein (GFP) gradually formed perinuclear massive aggregations, followed by cell death. However, it remains unclear how aggregate formation of mutant gamma PKC causes cell death. In the present study, we examined whether these mutant aggregations affect the ubiquitin-proteasome system (UPS) and endoplasmic reticular (ER) stress. Two mutant gamma PKC-GFPs (S119P and G128D) were strongly ubiquitinated, and dot-like aggregations of these mutants were ubiquitin-positive and colocalized with proteasome 20S. Furthermore, proteasome activity in cells with aggregates, especially massive ones, was significantly decreased. Aggregate formation of mutant gamma PKC-GFP induced phosphorylation of PERK (PKR-like ER kinase) and nuclear expression of CHOP (C/EBP homologous protein), hallmarks of ER stress and subsequently activated caspase-3. These results indicate that aggregate formation of mutant gamma PKC found in SCA14 impairs UPS and induces ER stress, leading to apoptotic cell death.
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PMID:Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress. 1800 63

We recently produced transgenic mice that expressed an abnormally expanded polyglutamine (polyQ) specifically in cerebellar Purkinje cells (polyQ mice). The polyQ mice showed inclusion body formation, cerebellar atrophy and severe ataxia. Here we analyzed polyQ mice using immunohistochemistry, immunoelectronmicroscopy and electrophysiology. A diffuse form of polyQ was detected in the nucleus. Interestingly, ubiquitinated large inclusions were located close to, but apparently outside of the soma of Purkinje cells. Infusion of lucifer yellow into Purkinje cells clearly indicated the traffic between the periplasmic inclusions and soma of Purkinje cells. To examine whether the formation of periplasmic inclusions was an active process or a result of cell death, the polyQ mouse cerebellum was immunolabeled for cleaved caspase-3, a marker of apoptosis. Interestingly, no Purkinje cells in P80 polyQ mice immunoreacted with the antibody. The results were substantiated by electrophysiological assay, which showed that P80 Purkinje cells with large periplasmic inclusions were functionally active: excitatory postsynaptic currents (EPSCs) were reliably evoked upon electrical stimulation of parallel fibers (PFs) or climbing fibers (CFs), and current injection into Purkinje cells generated action potentials; however, the frequency of action potentials in response to various volumes of current injection was consistently lower in polyQ mice than in wild-type animals, and aberrant innervation by multiple CFs was detected in polyQ mouse Purkinje cells. These results suggest that Purkinje cells with periplasmic inclusions were not apoptotic, but their functions were substantially impaired, which could contribute to the severe ataxic phenotype.
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PMID:Characterization of mutant mice that express polyglutamine in cerebellar Purkinje cells. 1910 74

We have identified a large expansion of an ATTCT repeat within intron 9 of ATXN10 on chromosome 22q13.31 as the genetic mutation of spinocerebellar ataxia type 10 (SCA10). Our subsequent studies indicated that neither a gain nor a loss of function of ataxin 10 is likely the major pathogenic mechanism of SCA10. Here, using SCA10 cells, and transfected cells and transgenic mouse brain expressing expanded intronic AUUCU repeats as disease models, we show evidence for a key pathogenic molecular mechanism of SCA10. First, we studied the fate of the mutant repeat RNA by in situ hybridization. A Cy3-(AGAAU)(10) riboprobe detected expanded AUUCU repeats aggregated in foci in SCA10 cells. Pull-down and co-immunoprecipitation data suggested that expanded AUUCU repeats within the spliced intronic sequence strongly bind to hnRNP K. Co-localization of hnRNP K and the AUUCU repeat aggregates in the transgenic mouse brain and transfected cells confirmed this interaction. To examine the impact of this interaction on hnRNP K function, we performed RT-PCR analysis of a splicing-regulatory target of hnRNP K, and found diminished hnRNP K activity in SCA10 cells. Cells expressing expanded AUUCU repeats underwent apoptosis, which accompanied massive translocation of PKCdelta to mitochondria and activation of caspase 3. Importantly, siRNA-mediated hnRNP K deficiency also caused the same apoptotic event in otherwise normal cells, and over-expression of hnRNP K rescued cells expressing expanded AUUCU repeats from apoptosis, suggesting that the loss of function of hnRNP K plays a key role in cell death of SCA10. These results suggest that the expanded AUUCU-repeat in the intronic RNA undergoes normal transcription and splicing, but causes apoptosis via an activation cascade involving a loss of hnRNP K activities, massive translocation of PKCdelta to mitochondria, and caspase 3 activation.
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PMID:Inactivation of hnRNP K by expanded intronic AUUCU repeat induces apoptosis via translocation of PKCdelta to mitochondria in spinocerebellar ataxia 10. 2054 52

In spinocerebellar ataxia-7 (SCA7), a polyglutamine (polyQ) expansion in the ataxin-7 protein leads to the formation of neuronal intranuclear inclusions (NIIs) and neurodegeneration. In this study, amyloid precursor-like protein 2 (APLP2) was identified as a partner protein for ataxin-7. APLP2, belonging to the APP gene family, undergoes secretase and caspase cleavages and has been implicated in the pathogenesis of Alzheimer's disease (AD). Activated caspase-3 cleaves APP family proteins to release N-terminal fragments (NTFs) and intracellular C-terminal domains (ICDs), which can translocate into the nucleus and induce neurotoxicity in AD. Here, we report abnormal nuclear relocation of APLP2 and detection of NTFs in NIIs in SCA7. The ICDs generated by caspase-3 cleavage of APLP2 accumulate in nuclei and contribute to a cumulative toxicity when coexpressed with mutated ataxin-7. Our data suggest that the interaction between APLP2 and ataxin-7 and proteolytic processing of APLP2 may contribute to the pathogenesis of SCA7.
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PMID:Amyloid precursor-like protein 2 cleavage contributes to neuronal intranuclear inclusions and cytotoxicity in spinocerebellar ataxia-7 (SCA7). 2073 23


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