期刊
NEURON
卷 55, 期 4, 页码 556-564出版社
CELL PRESS
DOI: 10.1016/j.neuron.2007.07.020
关键词
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资金
- NICHD NIH HHS [R37 HD20521, R37 HD020521, P30 HD24064, P30 HD024064] Funding Source: Medline
- NIMH NIH HHS [R01 MH076090] Funding Source: Medline
- NINDS NIH HHS [R01 NS051630-01A1, R01 NS051630-02, R01 NS051630] Funding Source: Medline
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 a 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 a 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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