title: RNA association and nucleocytoplasmic shuttling by ataxin-1.
abstract: Spinocerebellar ataxia type 1 (SCA1) is a dominant neurodegenerative disease caused by the expression of mutant ataxin-1 containing an expanded polyglutamine tract. Ataxin-1 is a nuclear protein that localizes to punctate inclusions similar to neuronal nuclear inclusions seen in many polyglutamine expansion disease proteins. We demonstrate that ataxin-1 localization to inclusions and inclusion dynamics within the nucleus are RNA and transcription dependent, but not dependent on the polyglutamine tract. Ataxin-1 nuclear inclusions are distinct from other described nuclear bodies but recruit the mRNA export factor, TAP/NXF1, in a manner that is enhanced by cell heat shock. By FRAP protein dynamic studies in live cells, we found that wild-type, but not mutant, ataxin-1 was capable of nuclear export. These results suggest that the normal role of ataxin-1 may be in RNA processing, perhaps nuclear RNA export. Thus, nuclear retention of mutant ataxin-1 may be an important toxic gain of function in SCA1 disease.
authors.affiliation: McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada.
authors.forename: Stuart
authors.initials: S
authors.lastname: Irwin
authors.forename: Mark
authors.initials: M
authors.lastname: Vandelft
authors.forename: Deborah
authors.initials: D
authors.lastname: Pinchev
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Howell
authors.forename: Joanna
authors.initials: J
authors.lastname: Graczyk
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: Ray
authors.initials: R
authors.lastname: Truant
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes; D006367:HeLa Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009930:Organic Chemicals; D012313:RNA / Q000378:metabolism*
chemical_list: C000593749:ATXN1 protein, human; C417664:Alexa594; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D005456:Fluorescent Dyes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009930:Organic Chemicals; D012313:RNA