Nuclear Accumulation of Stress Response mRNAs Contributes to the Neurodegeneration Caused by Fragile X Premutation rCGG Repeats

• Type of Material: Article
• Authors: Abrar Qurashi, Emory University; Wendi Li, Emory University; Jian-Ying Zhou, Emory University; Junmin Peng, Emory University; Peng Jin, Emory University
• Language: English
• Date: 2011-06-02
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Qurashi et al.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002102
• Title of Journal or Parent Work: PLoS Genetics
• ISSN: 1553-7390
• Volume: 7
• Issue: 6
• Start Page: e1002102
• End Page: e1002102
• Grant/Funding Information: PJ is supported by NIH grants R01 NS051630 and R01 MH076090.; PJ is a recipient of the Beckman Young Investigator Award and the Basil O'Connor Scholar Research Award, as well as an Alfred P. Sloan Research Fellow in Neuroscience.; JP is funded by NIH grants (P50AG025688 and P30NS055077).; AQ was supported by and is a recipient of a National Ataxia Postdoctoral Award.
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

Fragile X–associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that usually affects males over 50 years of age, and FXTAS patients are carriers of fragile X premutation alleles. Using a FXTAS Drosophila model, we previously showed that fragile X premutation rCGG repeats alone could cause neurodegeneration. Pur α and hnRNP A2/B1 were identified as specific premutation rCGG repeat-binding proteins (RBPs) that could bind and modulate fragile X premutation rCGG–mediated neuronal degeneration. Here, through systematic proteomic, genetic, and microarray analyses, we show that the nuclear accumulation of select mRNAs caused by fragile X premutation rCGG repeats may contribute to FXTAS pathogenesis, and the mechanism could be via impaired nuclear export due to the decreased levels of Rm62 seen upon fragile X premutation rCGG expression.