Abstract
The formation of intraneuronal inclusions is a common feature of neurodegenerative polyglutamine disorders, including Spinocerebellar ataxia type 3. The mechanism that triggers inclusion formation in these typically late onset diseases has remained elusive. However, there is increasing evidence that proteolytic fragments containing the expanded polyglutamine segment are critically required to initiate the aggregation process. We analyzed ataxin-3 proteolysis in neuroblastoma cells and in vitro and show that calcium-dependent calpain proteases generate aggregation-competent ataxin-3 fragments. Co-expression of the highly specific cellular calpain inhibitor calpastatin abrogated fragmentation and the formation of inclusions in cells expressing pathological ataxin-3. These findings suggest a critical role of calpains in the pathogenesis of Spinocerebellar ataxia type 3.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies
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Ataxin-3
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Calpain / antagonists & inhibitors*
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Calpain / metabolism
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Cell Line, Tumor
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Enzyme Inhibitors / pharmacology
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Humans
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Ionomycin / pharmacology
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Ionophores / pharmacology
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Kidney / cytology
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Machado-Joseph Disease / genetics*
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Machado-Joseph Disease / metabolism*
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Machado-Joseph Disease / pathology
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Mice
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / immunology
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Nerve Tissue Proteins / metabolism*
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Neuroblastoma
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology
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Nuclear Proteins / metabolism*
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Peptides / genetics*
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Rabbits
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Rats
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Repressor Proteins / genetics
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Repressor Proteins / immunology
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Repressor Proteins / metabolism*
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Transcription Factors / genetics
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Transcription Factors / immunology
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Transcription Factors / metabolism
Substances
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Antibodies
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Enzyme Inhibitors
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Ionophores
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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Repressor Proteins
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Transcription Factors
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polyglutamine
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Ionomycin
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ATXN3 protein, human
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Ataxin-3
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Atxn3 protein, mouse
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Calpain