Insights into the molecular basis of polyglutamine neurodegeneration from studies of a spinocerebellar ataxia type 7 mouse model

被引:9
作者
Grote, SK
La Spada, AR
机构
[1] Univ Washington, Dept Lab Med, Ctr Med, Seattle, WA 98195 USA
[2] Univ Washington, Dept Med, Ctr Med, Div Med Genet, Seattle, WA 98195 USA
[3] Univ Washington, Dept Neurol, Ctr Med, Div Neurogenet, Seattle, WA 98195 USA
关键词
D O I
10.1159/000072851
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Spinocerebellar ataxia type 7 (SCA7) is one member of a growing list of neurodegenerative disorders that are all caused by CAG repeat expansions that produce disease by encoding elongated polyglutamine tracts in a variety of apparently unrelated proteins. In this review, we provide an overview of our efforts to determine the molecular basis of polyglutamine neurotoxicity in SCA7 by modeling this polyglutamine repeat disorder in mice. We discuss how our SCA7 mouse model develops a phenotype that is reminiscent of the retinal and cerebellar disease pathology seen in human patients. All of these findings are considered in the context of numerous other models of polyglutamine disease pathology in mice and other organisms, together with various other in vitro and biochemical studies. We present the competing hypotheses of polyglutamine disease pathogenesis, and explain how our studies of SCA7 brainstem and retinal degeneration using this mouse model have yielded insights into possible mechanisms and pathways of polyglutamine disease pathology. In addition to illustrating how our SCA7 mouse model has allowed us to develop and advance notions of disease pathogenesis, we propose a model of polyglutamine molecular pathology that attempts to integrate the key observations in the field. We close by describing why our SCA7 mouse model should be useful for the next phase of polyglutamine disease research - the development of therapies, and predict that this stage of experimentation will continue to rely heavily on the mouse. Copyright (C) 2002 S.Karger AG, Basel.
引用
收藏
页码:164 / 174
页数:11
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