{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T10:57:30Z","timestamp":1789210650416,"version":"build-2803163510"},"reference-count":20,"publisher":"The Royal Society","issue":"1386","license":[{"start":{"date-parts":[[1999,6,29]],"date-time":"1999-06-29T00:00:00Z","timestamp":930614400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Phil. Trans. R. Soc. Lond. B"],"published-print":{"date-parts":[[1999,6,29]]},"abstract":"<jats:p>Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder characterized by progressive loss of coordination, motor impairment and the degeneration of cerebellar Purkinje cells, spinocerebellar tracts and brainstem nuclei. Many dominantly inherited neurodegenerative diseases share the mutational basis of SCA1: the expansion of a translated CAG repeat coding for glutamine. Mice lacking ataxin-1 display learning deficits and altered hippocampal synaptic plasticity but none of the abnormalities seen in human SCA1; mice expressing ataxin-1 with an expanded CAG tract (82 glutamine residues), however, develop Purkinje cell pathology and ataxia. These results suggest that mutant ataxin-1 gains a novel function that leads to neuronal degeneration. This novel function might involve aberrant interaction(s) with cell-specific protein(s), which in turn might explain the selective neuronal pathology. Mutant ataxin-1 interacts preferentially with a leucine-rich acidic nuclear protein that is abundantly expressed in cerebellar Purkinje cells and other brain regions affected in SCA1. Immunolocalization studies in affected neurons of patients and SCA1 transgenic mice showed that mutant ataxin-1 localizes to a single, ubiquitin-positive nuclear inclusion (NI) that alters the distribution of the proteasome and certain chaperones. Further analysis of NIs in transfected HeLa cells established that the proteasome and chaperone proteins co-localize with ataxin-1 aggregates. Moreover, overexpression of the chaperone HDJ-2\/HSDJ in HeLa cells decreased ataxin-1 aggregation, suggesting that protein misfolding might underlie NI formation. To assess the importance of the nuclear localization of ataxin-1 and its role in SCA1 pathogenesis, two lines of transgenic mice were generated. In the first line, the nuclear localization signal was mutated so that full-length mutant ataxin-1 would remain in the cytoplasm; mice from this line did not develop any ataxia or pathology. This suggests that mutant ataxin-1 is pathogenic only in the nucleus. To assess the role of the aggregates, transgenic mice were generated with mutant ataxin-1 without the self-association domain (SAD) essential for aggregate formation. These mice developed ataxia and Purkinje cell abnormalities similar to those seen in SCA1 transgenic mice carrying full-length mutant ataxin-1, but lacked NIs. The nuclear milieu is thus a critical factor in SCA1 pathogenesis, but large NIs are not needed to initiate pathogenesis. They might instead be downstream of the primary pathogenic steps. Given the accumulated evidence, we propose the following model for SCA1 pathogenesis: expansion of the polyglutamine tract alters the conformation of ataxin-1, causing it to misfold. This in turn leads to aberrant protein interactions. Cell specificity is determined by the cell-specific proteins interacting with ataxin-1. Submicroscopic protein aggregation might occur because of protein misfolding, and those aggregates become detectable as NIs as the disease advances. Proteasome redistribution to the NI might contribute to disease progression by disturbing proteolysis and subsequent vital cellular functions.<\/jats:p>","DOI":"10.1098\/rstb.1999.0462","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T19:55:21Z","timestamp":1027713321000},"page":"1079-1081","source":"Crossref","is-referenced-by-count":41,"title":["Progress in pathogenesis studies of spinocerebellar ataxia type 1"],"prefix":"10.1098","volume":"354","author":[{"given":"Christopher J.","family":"Cummings","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, Houston,TX 77030, USA"},{"name":"Program in Cell and Molecular Biology, Baylor College of Medicine, Houston,TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry T.","family":"Orr","sequence":"additional","affiliation":[{"name":"Departments of Laboratory Medicine and Pathology, and Biochemistry and Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda Y.","family":"Zoghbi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, Houston,TX 77030, USA"},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,TX 77030, USA"},{"name":"Howard HughesMedical Institute, Houston,TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[1999,6,29]]},"reference":[{"key":"p_1","doi-asserted-by":"crossref","unstructured":"Burright E. N. Clark H. B. Servadio A. Matilla T. Feddersen R. M. Yunis W. S. Duvick L. A. Zoghbi H. Y. & Orr H. T. 1995 SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82 937^948.","DOI":"10.1016\/0092-8674(95)90273-2"},{"key":"p_2","doi-asserted-by":"crossref","unstructured":"Burright E. N. Davidson J. D. Duvick L. A. Koshy B. Zoghbi H. Y. & Orr H. T. 1997 Identi\u00a2cation of a self-association region within the SCA1 gene product ataxin-1. Hum. Mol. Genet. 6 513^518.","DOI":"10.1093\/hmg\/6.4.513"},{"key":"p_3","doi-asserted-by":"crossref","unstructured":"Chung M.-y. Ranum L. P. W. Duvick L. Servadio A. Zoghbi H. Y. & Orr H. T. 1993 Analysis of the CAG repeat expansion in spinocerebellar ataxia type I: evidence for a possible mechanism predisposing to instability. Nature Genet. 5 254^258.","DOI":"10.1038\/ng1193-254"},{"key":"p_4","doi-asserted-by":"crossref","unstructured":"Cummings C. J. Mancini M. A. Antal\u00a1y B. DeFranco D. B. Orr H. T. & Zoghbi H. Y. 1998 Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature Genet. 19 148^154.","DOI":"10.1038\/502"},{"key":"p_5","doi-asserted-by":"crossref","unstructured":"Davies S. W. Turmaine M. Cozens B. A. DiFiglia M. Sharp A. H. Ross C. A. Scherzinger E. Wanker E. E. Mangiarini L. & Bates G. P. 1997 Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90 537^548.","DOI":"10.1016\/S0092-8674(00)80513-9"},{"key":"p_6","unstructured":"Green\u00a2eld J. G. 1954 The spino-cerebellar degenerations. Spring\u00a2eld IL: C. C. Thomas."},{"key":"p_7","doi-asserted-by":"publisher","DOI":"10.1007\/s004010050828"},{"key":"p_8","doi-asserted-by":"crossref","unstructured":"Holmberg M. (and 10 others) 1998 Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum. Mol. Genet. 7 913^918.","DOI":"10.1093\/hmg\/7.5.913"},{"key":"p_9","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81781-X"},{"key":"p_10","unstructured":"Koeppen A. H. & Barron K. D. 1984 The neuropathology of olivopontocerebellar atrophy. In The olivopontocerebellar atrophies (ed. R. C. Duvoisin & A. Plaitakis) pp. 13^38. New York: Raven."},{"key":"p_11","doi-asserted-by":"crossref","unstructured":"Li M. (and 10 others) 1998 Nuclear inclusions of the androgen receptor in spinal and bulbar muscular atrophy. Ann. Neurol. 44 249^254.","DOI":"10.1002\/ana.410440216"},{"key":"p_12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-14-05508.1998"},{"key":"p_13","doi-asserted-by":"crossref","unstructured":"Matilla T. Koshy B. Cummings C. J. Isobe T. Orr H. T. & Zoghbi H. Y. 1997 The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389 974^978.","DOI":"10.1038\/40159"},{"key":"p_14","doi-asserted-by":"crossref","unstructured":"Orr H. Chung M.-y. Ban\u00a2 S. Kwiatkowski  Jr T. J. Servadio A. Beaudet A. L. McCall A. E. Duvick L. A. Ranum L. P. W. & Zoghbi H. Y. 1993 Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellar ataxia type 1. Nature Genet. 4 221^226.","DOI":"10.1038\/ng0793-221"},{"key":"p_15","doi-asserted-by":"crossref","unstructured":"Paulson H. L. Perez M. K. Trottier Y. Trojanowsk J. Q. Subramony S. H. Das S. S. Vig P. Mandel J.-L. Fischbeck K. H. & Pittman R. N. 1997 Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19 333^334.","DOI":"10.1016\/S0896-6273(00)80943-5"},{"key":"p_16","doi-asserted-by":"crossref","unstructured":"Scherzinger E. Lurz R. Turmaine M. Mangiarini L. Hollenbach B. Hasenbank R. Bates G. P. Davies S. W. & Wanker E. E. 1997 Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. 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Neurol. 23 580^584.","DOI":"10.1002\/ana.410230609"}],"container-title":["Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.1999.0462","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.1999.0462","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:26:21Z","timestamp":1778621181000},"score":1,"resource":{"primary":{"URL":"http:\/\/royalsocietypublishing.org\/rstb\/article\/354\/1386\/1079-1081\/19475"}},"subtitle":[],"editor":[{"given":"M. F.","family":"Perutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]},{"given":"P. S.","family":"Harper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]},{"given":"M. A.","family":"Ferguson-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[1999,6,29]]},"references-count":20,"journal-issue":{"issue":"1386","published-print":{"date-parts":[[1999,6,29]]}},"alternative-id":["10.1098\/rstb.1999.0462"],"URL":"https:\/\/doi.org\/10.1098\/rstb.1999.0462","relation":{},"ISSN":["0962-8436","1471-2970"],"issn-type":[{"value":"0962-8436","type":"print"},{"value":"1471-2970","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,6,29]]}}}