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Author Notes:

Correspondence should be addressed to: swarren@genetics.emory.edu or pjin@genetics.emory.edu

These authors contributed equally.

Pur α binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of Fragile X Tremor/Ataxia Syndrome

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Journal Title:

Neuron

Volume:

Volume 55, Number 4

Publisher:

, Pages 556-564

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Summary Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently recognized neurodegenerative disorder in fragile X premutation carriers with FMR1 alleles containing 55-200 CGG repeats. Previously, we developed a Drosophila model of FXTAS and demonstrated that transcribed premutation repeats alone are sufficient to cause neurodegeneration, suggesting that rCGG repeat-binding proteins (RBPs) may be sequestered from their normal function by rCGG binding. Here we identify Pur α and hnRNP A2/B1 as RBPs. We show that Pur α and rCGG repeats interact in a sequence-specific fashion that is conserved between mammals and Drosophila. Overexpression of Pur α in Drosophila could suppress rCGG-mediated neurodegeneration in a dose-dependent manner. Furthermore, Pur α is also present in the inclusions of FXTAS patient brains. These findings support the disease mechanism of FXTAS of rCGG repeat sequestration of specific RBPs, leading to neuronal cell death, and implicate that Pur α plays important role in the pathogenesis of FXTAS.

Copyright information:

© 2007 Elsevier Inc. All rights reserved.

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