Search

Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited disorder characterized by cerebellum and brain stem neurodegeneration. CA7 is caused by a CAG/polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. We previously reported that directed expres ion 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 ofSCA7, we derived a conditional inactivation mouse model by inserting a loxP-flanked ataxin-7 cD A with 92 repeats into the translational start site of the murine prion protein (PrP) gene in a bacterial artificial chromo orne (BAC). The PrP-jloxed-SCA7-92QBACmice developed neurological disease, and exhibited cerebellar degeneration and BG proce s lo s. To inactivate polyQ-ataxin-7 expression in specific cerebellar cell types, we crossed PrP-jloxed-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 PC 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-jloxed-SCA7-92Q BA C triple transgenic mice, we noted a dramatic improvement in SCA7 disease phenotypes. These findings indicate that CA7 disease pathogenesis involves a convergence of alterations in a variety of different cell types to fully recapitulate the cerebellar degeneration. [ABSTRACT FROM AUTHOR]