Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae
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Animals
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Ataxin-1
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Ataxins
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Blotting, Northern
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Brain / metabolism
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Cells, Cultured
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Disease Models, Animal
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Gene Expression*
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Glutamine
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Immunohistochemistry
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Mice
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Mice, Transgenic
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Nerve Degeneration / genetics*
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Nerve Degeneration / therapy*
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Nerve Tissue Proteins / metabolism*
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Nerve Tissue Proteins / pharmacology
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Nuclear Proteins / metabolism*
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Nuclear Proteins / pharmacology
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Plasmids / genetics
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Psychomotor Performance / drug effects
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Purkinje Cells / drug effects
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Purkinje Cells / metabolism
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RNA Interference / physiology*
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RNA, Messenger / metabolism*
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / therapeutic use
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Reverse Transcriptase Polymerase Chain Reaction
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Spinocerebellar Ataxias / pathology*
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Transduction, Genetic
Substances
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Ataxin-1
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Ataxins
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Atxn1 protein, mouse
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Nerve Tissue Proteins
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Nuclear Proteins
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RNA, Messenger
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RNA, Small Interfering
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Glutamine