Abstract：
:Spinocerebellar ataxia type-3, also known as Machado-Joseph Disease, is one of many inherited neurodegenerative disorders caused by polyglutamine-encoding CAG repeat expansions in otherwise unrelated disease genes. Polyglutamine disorders are characterized by disease protein misfolding and aggregation; often within the nuclei of affected neurons. Although the precise mechanism of polyglutamine-mediated cell death remains elusive, evidence suggests that proteolysis of polyglutamine disease proteins by caspases contributes to pathogenesis. Using cellular models we now show that the endogenous spinocerebellar ataxia type-3 disease protein, ataxin-3, is proteolyzed in apoptotic paradigms, resulting in the loss of full-length ataxin-3 and the corresponding appearance of an approximately 28-kDa fragment containing the glutamine repeat. Broad-spectrum caspase inhibitors block ataxin-3 proteolysis and studies suggest that caspase-1 is a primary mediator of cleavage. Site-directed mutagenesis experiments eliminating three, six or nine potential caspase cleavage sites in the protein suggest redundancy in the site(s) at which cleavage can occur, as previously described for other disease proteins; but also map a major cleavage event to a cluster of aspartate residues within the ubiquitin-binding domain of ataxin-3 near the polyglutamine tract. Finally, caspase-mediated cleavage of expanded ataxin-3 resulted in increased ataxin-3 aggregation, suggesting a potential role for caspase-mediated proteolysis in spinocerebellar ataxia type-3 pathogenesis.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Berke SJ,Schmied FA,Brunt ER,Ellerby LM,Paulson HLdoi
10.1111/j.1471-4159.2004.02369.xkeywords:
subject
Has Abstractpub_date
2004-05-01 00:00:00pages
908-18issue
4eissn
0022-3042issn
1471-4159pii
JNC2369journal_volume
89pub_type
杂志文章abstract：:To evaluate the ability of ependymal, microglial and oligodendroglial cells to degrade leucine, the presence of 3-methylcrotonyl-CoA carboxylase (MCC) was investigated in cultures of these cells. MCC is a biotin-containing heterodimeric enzyme that is specific for the irreversible part of the leucine catabolic pathway...
journal_title：Journal of neurochemistry
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doi：10.1111/j.1471-4159.2006.03819.x
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1983.tb11322.x
更新日期：1983-02-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1989.tb10932.x
更新日期：1989-01-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2001.00025.x
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1992.tb10980.x
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2001.00405.x
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1984.tb02679.x
更新日期：1984-02-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章,评审
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更新日期：2010-01-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
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更新日期：1991-11-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/jnc.14591
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pub_type： 杂志文章
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更新日期：2016-07-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1987.tb03401.x
更新日期：1987-07-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/jnc.12959
更新日期：2015-04-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/jnc.13034
更新日期：2015-04-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1998.71041396.x
更新日期：1998-10-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2001.00447.x
更新日期：2001-08-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2005.03418.x
更新日期：2005-11-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1992.tb08437.x
更新日期：1992-10-01 00:00:00
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journal_title：Journal of neurochemistry
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doi：10.1046/j.1471-4159.1994.63062202.x
更新日期：1994-12-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1984.tb05402.x
更新日期：1984-11-01 00:00:00
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journal_title：Journal of neurochemistry
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更新日期：1989-01-01 00:00:00
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pub_type： 杂志文章
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更新日期：2003-11-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1983.tb04769.x
更新日期：1983-08-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1985.tb07148.x
更新日期：1985-01-01 00:00:00
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journal_title：Journal of neurochemistry
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doi：10.1111/j.1471-4159.1992.tb09409.x
更新日期：1992-08-01 00:00:00
