title: RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.
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.
authors.affiliation: Program in Gene Therapy, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Haibin
authors.initials: H
authors.lastname: Xia
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Mao
authors.forename: Steven L
authors.initials: SL
authors.lastname: Eliason
authors.forename: Scott Q
authors.initials: SQ
authors.lastname: Harper
authors.forename: Inês H
authors.initials: IH
authors.lastname: Martins
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
authors.forename: Linda
authors.initials: L
authors.lastname: Yang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kotin
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D005973:Glutamine; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000628:therapy*; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism* / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011597:Psychomotor Performance / Q000187:drug effects; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000473:pathology*; D014161:Transduction, Genetic
chemical_list: D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D005973:Glutamine