title: Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3).
abstract: Spinocerebellar ataxia type 3 (SCA3) is pathologically characterized by the formation of intranuclear aggregates which contain ataxin-3, the mutated protein in SCA3, in a specific subtype of neurons. It has been proposed that ataxin-3 is cleaved by proteolytic enzymes, in particular by calpains and caspases, eventually leading to the formation of aggregates. In our study, we examined the ability of calpains to cleave ataxin-3 in vitro and in vivo. We demonstrated in cell culture and mouse brain homogenates that cleavage of overexpressed ataxin-3 by calpains and in particular by calpain-2 occur and that polyglutamine expanded ataxin-3 is more sensitive to calpain degradation. Based on these results, we investigated the influence of calpains on the pathogenesis of SCA3 in vivo. For this purpose, we enhanced calpain activity in a SCA3 transgenic mouse model by knocking out the endogenous calpain inhibitor calpastatin. Double-mutant mice demonstrated an aggravated neurological phenotype with an increased number of nuclear aggregates and accelerated neurodegeneration in the cerebellum. This study confirms the critical importance of calcium-dependent calpain-type proteases in the pathogenesis of SCA3 and suggests that the manipulation of the ataxin-3 cleavage pathway and the regulation of intracellular calcium homeostasis may represent novel targets for therapeutic intervention in SCA3.
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany. jeannette.huebener@med.uni-tuebingen.de
authors.forename: Jeannette
authors.initials: J
authors.lastname: Hübener
authors.forename: Jonasz Jeremiasz
authors.initials: JJ
authors.lastname: Weber
authors.forename: Claudia
authors.initials: C
authors.lastname: Richter
authors.forename: Lisa
authors.initials: L
authors.lastname: Honold
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.forename: Fabronia
authors.initials: F
authors.lastname: Murad
authors.forename: Peter
authors.initials: P
authors.lastname: Breuer
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
authors.forename: Peter
authors.initials: P
authors.lastname: Bellstedt
authors.forename: Francois
authors.initials: F
authors.lastname: Paquet-Durand
authors.forename: Jiro
authors.initials: J
authors.lastname: Takano
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Huu Phuc
authors.initials: HP
authors.lastname: Nguyen
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D002118:Calcium / Q000737:chemistry; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D005838:Genotype; D006023:Glycoproteins / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; C039304:calpain inhibitors; C097188:polyglutamine; C033668:calpastatin; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; D002154:Calpain; D002118:Calcium