Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1

Xi Lin, Barbara Antalffy, Dongcheul Kang, Harry T. Orr, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

331 Scopus citations


The expansion of an unstable CAG repeat causes spinocerebellar ataxia type 1 (SCA1) and several other neurodegenerative diseases. How polyglutamine expansions render the resulting proteins toxic to neurons, however, remains elusive. Hypothesizing that long polyglutamine tracts alter gene expression, we found certain neuronal genes involved in signal transduction and calcium homeostasis sequentially downregulated in SCA1 mice. These genes were abundant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was mediated by expanded ataxin-1 and occured before detectable pathology. Similar downregulation occurred in SCA1 human tissues. Altered gene expression may be the earliest mediator of polyglutamine toxicity.

Original languageEnglish (US)
Pages (from-to)157-163
Number of pages7
JournalNature neuroscience
Issue number2
StatePublished - Feb 2000

Bibliographical note

Funding Information:
The authors thank A. Beaudet for providing the Ube3a null mice, M. Philips at New York University School of Medicine and K. Tanaka at the National Institute of Neuroscience in Japan for providing the anti-PCCMT and anti-EAAT4 antibodies, H. J. Bellen for reading the manuscript and V. Brandt for comments. This work was supported by grants NS27699 and NS22920 from the National Institutes of Health (to H.Y.Z. and H.T.O.) and by the core facilities of the Baylor College of Medicine Mental Retardation Research Center. X. Lin is an Associate and H. Zoghbi an Investigator with the Howard Hughes Medical Institute.


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