Abstract
Spinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant late onset neurodegenerative disease caused by an expanded polyglutamine tract in ataxin-1. Here, we compared the protective effects of overexpressing ataxin-1-like using recombinant AAVs, or reducing expression of mutant ataxin-1 using virally delivered RNA interference (RNAi), in a transgenic mouse model of SCA1. For the latter, we used an artificial microRNA (miR) design that optimizes potency, efficacy and safety to suppress ataxin-1 expression (miS1). Delivery of either ataxin-1-like or miS1 viral vectors to SCA1 mice cerebella resulted in widespread cerebellar Purkinje cell transduction and improved behavioral and histological phenotypes. Our data indicate the utility of either approach as a possible therapy for SCA1 patients.
Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxin-1
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Ataxins
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Behavior, Animal / physiology
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Blotting, Western
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Brain / pathology
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Dependovirus / genetics
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Gait / physiology
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Genetic Vectors
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HEK293 Cells
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Humans
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Immunohistochemistry
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Immunoprecipitation
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In Situ Hybridization
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Locomotion / physiology
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Mice
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Mice, Transgenic
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MicroRNAs / biosynthesis
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MicroRNAs / genetics
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Nerve Tissue Proteins / biosynthesis*
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Nerve Tissue Proteins / genetics
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Nuclear Proteins / biosynthesis*
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Nuclear Proteins / genetics
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Plasmids
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Postural Balance / physiology
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RNA Interference / physiology*
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RNA, Small Interfering / therapeutic use
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Real-Time Polymerase Chain Reaction
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Spinocerebellar Ataxias / pathology
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Spinocerebellar Ataxias / psychology
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Spinocerebellar Ataxias / therapy*
Substances
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ATXN1 protein, human
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Ataxin-1
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Ataxins
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Atxn1 protein, mouse
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MicroRNAs
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Nerve Tissue Proteins
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Nuclear Proteins
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RNA, Small Interfering