title: Spinocerebellar ataxia type 7 cerebellar disease requires the coordinated action of mutant ataxin-7 in neurons and glia, and displays non-cell-autonomous bergmann glia degeneration.
abstract: Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited disorder characterized by cerebellum and brainstem neurodegeneration. SCA7 is caused by a CAG/polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. We previously reported that directed expression of polyQ-ataxin-7 in Bergmann glia (BG) in transgenic mice leads to ataxia and non-cell-autonomous Purkinje cell (PC) degeneration. To further define the cellular basis of SCA7, we derived a conditional inactivation mouse model by inserting a loxP-flanked ataxin-7 cDNA with 92 repeats into the translational start site of the murine prion protein (PrP) gene in a bacterial artificial chromosome (BAC). The PrP-floxed-SCA7-92Q BAC mice developed neurological disease, and exhibited cerebellar degeneration and BG process loss. To inactivate polyQ-ataxin-7 expression in specific cerebellar cell types, we crossed PrP-floxed-SCA7-92Q BAC mice with Gfa2-Cre transgenic mice (to direct Cre to BG) or Pcp2-Cre transgenic mice (which yields Cre in PCs and inferior olive). Excision of ataxin-7 from BG partially rescued the behavioral phenotype, but did not prevent BG process loss or molecular layer thinning, while excision of ataxin-7 from PCs and inferior olive provided significantly greater rescue and prevented both pathological changes, revealing a non-cell-autonomous basis for BG pathology. When we prevented expression of mutant ataxin-7 in BG, PCs, and inferior olive by deriving Gfa2-Cre;Pcp2-Cre;PrP-floxed-SCA7-92Q BAC triple transgenic mice, we noted a dramatic improvement in SCA7 disease phenotypes. These findings indicate that SCA7 disease pathogenesis involves a convergence of alterations in a variety of different cell types to fully recapitulate the cerebellar degeneration.
authors.affiliation: Department of Neurology, Biochemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Furrer
authors.forename: Mathini S
authors.initials: MS
authors.lastname: Mohanachandran
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Waldherr
authors.forename: Christopher
authors.initials: C
authors.lastname: Chang
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Damian
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000067719:Ataxin-7; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D011328:Prions / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D045442:Rotarod Performance Test; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides; D011328:Prions; D012333:RNA, Messenger; C097188:polyglutamine
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