Pur Alpha Binds to RCGG Repeats and Modulates Repeat-mediated Neurodegeneration in a Drosophila Model of Fragile X Tremor/ataxia Syndrome

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2007 Aug 19

PMID 17698009

Citations 195

Authors

Peng Jin

Ranhui Duan

Abrar Qurashi

Yunlong Qin

Donghua Tian

Tracie C Rosser

Huijie Liu

Yue Feng

Stephen T Warren

Affiliations

Soon will be listed here.

Abstract

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 alpha and hnRNP A2/B1 as RBPs. We show that Pur alpha and rCGG repeats interact in a sequence-specific fashion that is conserved between mammals and Drosophila. Overexpression of Pur alpha in Drosophila could suppress rCGG-mediated neurodegeneration in a dose-dependent manner. Furthermore, Pur alpha 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 alpha plays an important role in the pathogenesis of FXTAS.

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