Overexpression of HGF attenuates the degeneration of Purkinje cells and Bergmann glia in a knockin mouse model of spinocerebellar ataxia type 7

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• 作者：Satsuki Noma^a ; ^b ; Wakana Ohya-Shimada^a ; Masaaki Kanai^a ; Keiji Ueda^b ; Toshikazu Nakamura^c ; Hiroshi Funakoshi^a ; ^{hfuna@asahikawa-med.ac.jp}
• 关键词：Hepatocyte growth factor ; c-Met ; Polyglutamine disease ; Glutamate transporter ; GLAST ; GLT-1 ; SCA
• 刊名：Neuroscience Research
• 出版年：2012
• 期刊代码：53_01680102
• 类别：neu
• 出版时间：June, 2012
• 卷：73
• 期：2
• 页码：115-121
• 文件大小：1173 K

摘要

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.