Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome.
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.
Jin
Peng
P
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. pjin@genetics.emory.edu
Duan
Ranhui
R
Qurashi
Abrar
A
Qin
Yunlong
Y
Tian
Donghua
D
Rosser
Tracie C
TC
Liu
Huijie
H
Feng
Yue
Y
Warren
Stephen T
ST
D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005123:Eye / Q000473:pathology / Q000648:ultrastructure; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008855:Microscopy, Electron, Scanning / Q000379:methods; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; D018840:HSP70 Heat-Shock Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C545199:Pur-alpha protein, Drosophila; C076035:c-MYC-associated zinc finger protein
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