RNA association and nucleocytoplasmic shuttling by ataxin-1.
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.
Irwin
Stuart
S
McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada.
Vandelft
Mark
M
Pinchev
Deborah
D
Howell
Jenny L
JL
Graczyk
Joanna
J
Orr
Harry T
HT
Truant
Ray
R
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*
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