title: Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3.
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.
authors.affiliation: Neuroscience Graduate Program and Department of Neurology, University of Iowa, Iowa City, Iowa 52242, USA. sarah-berke@uiowa.edu
authors.forename: Sarah J Shoesmith
authors.initials: SJ
authors.lastname: Berke
authors.forename: Francisca A Flores
authors.initials: FA
authors.lastname: Schmied
authors.forename: Ewout R
authors.initials: ER
authors.lastname: Brunt
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000067699:Ataxin-3; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism; D010455:Peptides / Q000235:genetics*; D051381:Rats; D012097:Repressor Proteins; D014157:Transcription Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; C511593:Atxn3 protein, rat; D020169:Caspases; D020170:Caspase 1