Hexanucleotide Repeats in ALS/FTD Form Length-Dependent RNA Foci, Sequester RNA Binding Proteins, and Are Neurotoxic

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• 作者：Youn-Bok Lee ; Han-Jou Chen ; Jo茫o聽N. Peres ; Jorge Gomez-Deza ; Jan Attig ; Maja 艩talekar ; Claire Troakes ; Agnes聽L. Nishimura ; Emma聽L. Scotter ; Caroline Vance ; Yoshitsugu Adachi ; Valentina Sardone ; Jack聽W. Miller ; Bradley聽N. Smith ; Jean-Marc Gallo ; Jernej Ule ; Frank Hirth ; Boris Rogelj ; Corinne Houart ; Christopher聽E. Shaw ; et al.
• 刊名：Cell Reports
• 出版年：12 December, 2013
• 年：2013
• 卷：5
• 期：5
• 页码：1178-1186
• 全文大小：2212 K

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Summary

The GGGGCC (G4C2) intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Intranuclear neuronal RNA foci聽have been observed in ALS and FTD tissues, suggesting that G4C2 RNA may be toxic. Here, we demonstrate that the expression of 38脳 and 72脳 G4C2 repeats form intranuclear RNA foci that initiate apoptotic cell death in neuronal cell lines and zebrafish embryos. The foci colocalize with a subset of RNA binding proteins, including SF2, SC35, and hnRNP-H in transfected cells. Only hnRNP-H binds directly to G4C2 repeats following RNA immunoprecipitation, and only hnRNP-H colocalizes with 70% of G4C2 RNA foci detected in C9ORF72 mutant ALS and FTD brain tissues. We show that expanded G4C2 repeats are potently neurotoxic and bind hnRNP-H and other RNA binding proteins. We propose that RNA toxicity and protein sequestration may disrupt RNA processing and contribute to neurodegeneration.