To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse, we targeted 154 CAG repeats into the endogenous mouse locus. Sca1154Q/2Q mice developed a progressive neurological disorder that resembles human SCA1, featuring motor incoordination, cognitive deficits, wasting, and premature death, accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region, being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells, the most affected in SCA1, did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.
Copyright © 2002 Cell Press.
Neuron, Vol 34, 905-919, 13 June 2002
Article
A Long CAG Repeat in the Mouse Sca1 Locus Replicates SCA1 Features and Reveals the Impact of Protein Solubility on Selective Neurodegeneration
1Department of Molecular and Human Genetics, Houston, TX 77030 USA
2Division of Neuroscience, Houston, TX 77030 USA
3Department of Pathology, Houston, TX 77030 USA
4Department of Pediatrics, Houston, TX 77030 USA
5Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA
6Department of Cellular Neurophysiology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan
7Institute of Human Genetics, University of Minnesota, Mayo Mail Code 206, Minneapolis, MN 55455 USA
Corresponding author
Huda Y. Zoghbi
(713) 798-6558 (phone)
(713) 798-8728 (fax)
hzoghbi@bcm.tmc.edu
Summary
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