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: Satsuki Noma, Wakana Ohya-Shimada, Masaaki Kanai, Keiji Ueda, Toshikazu Nakamura, Hiroshi Funakoshi
• Journal: Neuroscience research (Neurosci Res) Vol. 73 Issue 2 Pg. 115-21 (Jun 2012) ISSN: 1872-8111 [Electronic] Ireland
• PMID: 22426494 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Chemical References

• HGF protein, mouse
• Hepatocyte Growth Factor

Topics

• Animals
• Cells, Cultured
• Disease Models, Animal
• Female
• Gene Expression Regulation
• Gene Knock-In Techniques
• Hepatocyte Growth Factor (biosynthesis, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Degeneration (genetics, metabolism, pathology)
• Neuroglia (metabolism, pathology)
• Pregnancy
• Purkinje Cells (metabolism, pathology)
• Spinocerebellar Ataxias (genetics, metabolism, pathology)