title: Overexpression of HGF attenuates the degeneration of Purkinje cells and Bergmann glia in a knockin mouse model of spinocerebellar ataxia type 7.
abstract: Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder associated with cerebellar neurodegeneration caused by expansion of a CAG repeat in the ataxin-7 gene. Hepatocyte growth factor (HGF), a pleiotrophic growth factor, displays highly potent neurotrophic activities on cerebellar neurons. A mutant c-met/HGF receptor knockin mouse model has revealed a role for HGF in the postnatal development of the cerebellum. The present study was designed to elucidate the effect of HGF on cerebellar neurodegeneration in a knockin mouse model of SCA7 (SCA7-KI mouse). SCA7-KI mice were crossed with transgenic mice overexpressing HGF (HGF-Tg mice) to produce SCA7-KI/HGF-Tg mice that were used to examine the phenotypic differences following HGF overexpression. The Purkinje cellular degeneration is thought to occur via cell-autonomous and non-cell autonomous mechanisms mediated by a reduction of glutamate transporter levels in Bergmann glia. The Purkinje cellular degeneration and reduced expression of glutamate transporters in the cerebellum of SCA7-KI mice were largely attenuated in the SCA7-KI/HGF-Tg mice. Moreover, phenotypic impairments exhibited by SCA7-KI mice during rotarod tests were alleviated in SCA7-KI/HGF-Tg mice. The bifunctional nature of HGF on both Purkinje cells and Bergmann glia highlight the potential therapeutic utility of this molecule for the treatment of SCA7 and related disorders.
authors.affiliation: Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Noma
authors.forename: Wakana
authors.initials: W
authors.lastname: Ohya-Shimada
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kanai
authors.forename: Keiji
authors.initials: K
authors.lastname: Ueda
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Funakoshi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C553307:HGF protein, mouse; D017228:Hepatocyte Growth Factor