title: Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies.
abstract: Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, The Netherlands.
authors.forename: Melvin M
authors.initials: MM
authors.lastname: Evers
authors.forename: Lodewijk J A
authors.initials: LJ
authors.lastname: Toonen
authors.forename: Willeke M C
authors.initials: WM
authors.lastname: van Roon-Mom
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D000067699:Ataxin-3; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000633:toxicity*; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: D000975:Antioxidants; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine; D012313:RNA; C092341:ATXN3 protein, human; D000067699:Ataxin-3