RNA-mediated toxicity in C9orf72 ALS and FTD

NEUROBIOLOGY OF DISEASE

卷:145

Review

McEachin, Zachary T.^1,2  Parameswaran, Janani¹  Raj, Nisha^1,2  Bassell, Gary J.^1,2,3  Jiang, Jie¹ 

[1] Emory Univ, Dept Cell Biol, Atlanta, GA 30322 USA

[2] Emory Univ, Lab Translat Cell Biol, Atlanta, GA 30322 USA

[3] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA

关键词: Amyotrophic lateral sclerosis;    Frontotemporal dementia;    C9orf72;    RNA-mediated toxicity;    RNA foci;    Dipeptide repeat proteins;    Antisense oligonucleotide;   

DOI  :  10.1016/j.nbd.2020.105055

来源: Elsevier

【 摘 要 】

A GGGGCC hexanucleotide repeat expansion in the first intron of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Compelling evidence suggests that gain of toxicity from the bidirectionally transcribed repeat expanded RNAs plays a central role in disease pathogenesis. Two potential mechanisms have been proposed including RNA-mediated toxicity and/or the production of toxic dipeptide repeat proteins. In this review, we focus on the role of RNA mediated toxicity in ALS/FTD caused by the C9orf72 mutation and discuss arguments for and against this mechanism. In addition, we summarize how G4C2 repeat RNAs can elicit toxicity and potential therapeutic strategies to mitigate RNA-mediated toxicity.