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

301 Scopus citations

Abstract

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
Volume3
Issue number2
DOIs
StatePublished - Feb 1 2000

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