Nature Neuroscience
3, 157 - 163 (2000)
doi:10.1038/72101
Polyglutamine expansion down-regulates specific neuronal genes before
pathologic changes in SCA1Xi Lin1, 2, Barbara Antalffy3, Dongcheul Kang1, 2, Harry T. Orr4
& Huda Y. Zoghbi1, 21
Howard Hughes Medical Institute, Baylor College of
Medicine, One Baylor Plaza, Houston,
Texas 77030, USA
2
Department of Molecular and Human Genetics, Baylor
College of Medicine, One Baylor Plaza, Houston
, Texas 77030, USA
3
Department of Pathology, Baylor College of Medicine
, One Baylor Plaza, Houston, Texas
77030, USA
4
Department of Laboratory Medicine and Pathology, Institute
of Human Genetics, University of Minnesota, Harvard Street at
East River Rd., Minneapolis, Minnesota
55455, USA
Correspondence should be addressed to Huda Y. Zoghbi hzoghbi@bcm.tmc.eduThe 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.
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