Pur [alpha] Binds to rCGG Repeats and Modulates Repeat-Mediated Neurodegeneration in a Drosophila Model of Fragile X Tremor/Ataxia Syndrome

• Published in: Neuron (Cambridge, Mass.) Vol. 55; no. 4; p. 556
• Main Authors: Jin, Peng, Duan, Ranhui, Qurashi, Abrar, Qin, Yunlong, Tian, Donghua, Rosser, Tracie C, Liu, Huijie, Feng, Yue, Warren, Stephen T
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Limited 16.08.2007
• Subjects: Ataxia; Brain research; Deoxyribonucleic acid; DNA; Insects; Mutation; Neurodegeneration; Neuropathology; Pathogenesis; Proteins; Scanning electron microscopy
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2007.07.020

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently recognized neurodegenerative disorder in fragile X premutation carriers withFMR1alleles containing 55-200 CGG repeats. Previously, we developed aDrosophilamodel 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 andDrosophila. Overexpression of Pur α inDrosophilacould 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 an important role in the pathogenesis of FXTAS.