Cytogenetic and Genome Research

 

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

Grote S.K.a · La Spada A.R.a,b,c

Author affiliations

Departments of aLaboratory Medicine, bMedicine (Division of Medical Genetics), cNeurology (Division of Neurogenetics), University of Washington Medical Center, Seattle WA (USA)

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Cytogenet Genome Res 100:164–174 (2003)
https://doi.org/10.1159/000072851

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Article / Publication Details

First-Page Preview
Abstract of Paper

Received: November 22, 2002
Accepted: January 20, 2003
Published online: October 15, 2003
Issue release date: 2003

Number of Print Pages: 11
Number of Figures: 4
Number of Tables: 0

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: https://www.karger.com/CGR

Abstract

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.   

© 2003 S. Karger AG, Basel



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Article / Publication Details

First-Page Preview
Abstract of Paper

Received: November 22, 2002
Accepted: January 20, 2003
Published online: October 15, 2003
Issue release date: 2003

Number of Print Pages: 11
Number of Figures: 4
Number of Tables: 0

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: https://www.karger.com/CGR

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A.R.L. is supported by grant R01-EY14061 from the NIH for this work, and is the recipient of a Beeson Physician Scholar Award from the American Federation for Aging Research.
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