RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia

Haibin Xia, Qinwen Mao, Steven L. Eliason, Scott Q. Harper, Inês H. Martins, Harry T. Orr, Henry L. Paulson, Linda Yang, Robert M. Kotin, Beverly L. Davidson

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604 Scopus citations


The dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatable, neurodegenerative disorders. In inducible mouse models of SCA1 and Huntington disease, repression of mutant allele expression improves disease phenotypes. Thus, therapies designed to inhibit expression of the mutant gene would be beneficial. Here we evaluate the ability of RNA interference (RNAi) to inhibit polyglutamine-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1. Upon intracerebellar injection, recombinant adeno-associated virus (AAV) vectors expressing short hairpin RNAs profoundly improved motor coordination, restored cerebellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice. Our data demonstrate in vivo the potential use of RNAi as therapy for dominant neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)816-820
Number of pages5
JournalNature Medicine
Issue number8
StatePublished - Aug 2004

Bibliographical note

Funding Information:
We thank C. McLennan, J. Critchfield, S. Ries, N. Kiewiet and X. He for assistance. This work was supported by the National Institutes of Health (B.L.D., H.L.P. and H.T.O.), the Hereditary Disease Foundation (B.L.D., H.L.P. and S.Q.H.) and the Roy J. Carver Charitable Trust (B.L.D.).


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