title: A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript.
abstract: Polyglutamine diseases, including spinocerebellar ataxia type 3 (SCA3), are caused by CAG repeat expansions that encode abnormally long glutamine repeats in the respective disease proteins. While the mechanisms underlying neurodegeneration remain uncertain, evidence supports a proteotoxic role for the mutant protein dictated in part by the specific genetic and protein context. To further define pathogenic mechanisms in SCA3, we generated a mouse model in which a CAG expansion of 82 repeats was inserted into the murine locus by homologous recombination. SCA3 knockin mice exhibit region-specific aggregate pathology marked by intranuclear accumulation of the mutant Atxn3 protein, abundant nuclear inclusions and, in select brain regions, extranuclear aggregates localized to neuritic processes. Knockin mice also display altered splicing of the disease gene, promoting expression of an alternative isoform in which the intron immediately downstream of the CAG repeat is retained. In an independent mouse model expressing the full human ATXN3 disease gene, expression of this alternatively spliced transcript is also enhanced. These results, together with recent findings in other polyglutamine diseases, suggest that CAG repeat expansions can promote aberrant splicing to produce potentially more aggregate-prone isoforms of the disease proteins. This report of a SCA3 knockin mouse expands the repertoire of existing models of SCA3, and underscores the potential contribution of alternative splicing to disease pathogenesis in SCA3 and other polyglutamine disorders.
authors.affiliation: Department of Neurology, Medical Scientist Training Program and Neuroscience Graduate Program.
authors.forename: Biswarathan
authors.initials: B
authors.lastname: Ramani
authors.affiliation: Medical Scientist Training and Cellular and Molecular Biology Graduate Programs, University of Iowa College of Medicine, IA, USA.
authors.forename: Ginny M
authors.initials: GM
authors.lastname: Harris
authors.affiliation: Department of Neurology.
authors.forename: Rogerio
authors.initials: R
authors.lastname: Huang
authors.affiliation: Department of Neurology.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.affiliation: Molecular and Integrative Physiology.
authors.forename: Geoffrey G
authors.initials: GG
authors.lastname: Murphy
authors.affiliation: Department of Neurology.
authors.forename: Maria do Carmo
authors.initials: Mdo C
authors.lastname: Costa
authors.affiliation: Department of Neurology.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Internal Medicine.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Saunders
authors.affiliation: Department of Neurology, University of Florida, Gainesville, FL, USA.
authors.forename: Guangbin
authors.initials: G
authors.lastname: Xia
authors.affiliation: Department of Computational Medicine & Bioinformatics, University of Michigan, MI, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: McEachin
authors.affiliation: Department of Neurology, henryp@med.umich.edu.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000067699:Ataxin-3; D001483:Base Sequence; D002460:Cell Line; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055879:Gene Knock-In Techniques; D056426:Genetic Loci; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse