{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:04:03Z","timestamp":1791317043357,"version":"4.3.1"},"reference-count":46,"publisher":"The Company of Biologists","issue":"1","license":[{"start":{"date-parts":[[2005,7,1]],"date-time":"2005-07-01T00:00:00Z","timestamp":1120176000000},"content-version":"vor","delay-in-days":181,"URL":"http:\/\/www.biologists.com\/user-licence-1-1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,1,1]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1242\/jcs.01611","type":"journal-article","created":{"date-parts":[[2004,12,22]],"date-time":"2004-12-22T22:08:44Z","timestamp":1103753324000},"page":"233-242","source":"Crossref","is-referenced-by-count":103,"title":["RNA association and nucleocytoplasmic shuttling by ataxin-1"],"prefix":"10.1242","volume":"118","author":[{"given":"Stuart","family":"Irwin","sequence":"first","affiliation":[{"name":"McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Vandelft","sequence":"additional","affiliation":[{"name":"McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Pinchev","sequence":"additional","affiliation":[{"name":"McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny L.","family":"Howell","sequence":"additional","affiliation":[{"name":"McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Graczyk","sequence":"additional","affiliation":[{"name":"McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry T.","family":"Orr","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology and the Institute of Human Genetics, University of Minnesota, MN 55455-0213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ray","family":"Truant","sequence":"additional","affiliation":[{"name":"McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042518535165700_REF1","doi-asserted-by":"crossref","unstructured":"Brown, V., Jin, P., Ceman, S., Darnell, J. 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Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell113, 457-468.","DOI":"10.1016\/S0092-8674(03)00349-0"},{"key":"2021042518535165700_REF7","doi-asserted-by":"crossref","unstructured":"Chen, Y. W., Allen, M. D., Veprintsev, D. B., Lowe, J. and Bycroft, M. (2004). The structure of the AXH domain of spinocerebellar ataxin-1. J. Biol. Chem.279, 3758-3765.","DOI":"10.1074\/jbc.M309817200"},{"key":"2021042518535165700_REF8","doi-asserted-by":"crossref","unstructured":"Cummings, C. J. and Zoghbi, H. Y. (2000). Fourteen and counting: unraveling trinucleotide repeat diseases. Hum. Mol. Genet.9, 909-916.","DOI":"10.1093\/hmg\/9.6.909"},{"key":"2021042518535165700_REF9","doi-asserted-by":"crossref","unstructured":"Cummings, C. J., Mancini, M. A., Antalffy, B., DeFranco, D. B., Orr, H. T. and Zoghbi, H. Y. (1998). 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