A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration

Kei Watase, Edwin J. Weeber, Bisong Xu, Barbara Antalffy, Lisa Yuva-Paylor, Kouichi Hashimoto, Masanobu Kano, Richard Atkinson, Yaling Sun, Dawna L. Armstrong, J. David Sweatt, Harry T. Orr, Richard Paylor, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

216 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)905-919
Number of pages15
JournalNeuron
Volume34
Issue number6
DOIs
StatePublished - Jun 13 2002

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