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Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article number664151
Pages (from-to)664151
JournalFrontiers in cellular neuroscience
Published21 Apr 2021

Bibliographical note

Funding Information: This work was supported by the UK Dementia Research Institute which receives its funding from DRI Limited, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Publisher Copyright: © Copyright © 2021 Solomon, Smikle, Reid and Mizielinska. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Since the discovery of the C9orf72 repeat expansion mutation as causative for chromosome 9-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in 2011, a multitude of cellular pathways have been implicated. However, evidence has also been accumulating for a key mechanism of cellular compartmentalization-phase separation. Liquid-liquid phase separation (LLPS) is fundamental for the formation of membraneless organelles including stress granules, the nucleolus, Cajal bodies, nuclear speckles and the central channel of the nuclear pore. Evidence has now accumulated showing that the formation and function of these membraneless organelles is impaired by both the toxic arginine rich dipeptide repeat proteins (DPRs), translated from the C9orf72 repeat RNA transcript, and the repeat RNA itself. Both the arginine rich DPRs and repeat RNA themselves undergo phase separation and disrupt the physiological phase separation of proteins involved in the formation of these liquid-like organelles. Hence abnormal phase separation may explain a number of pathological cellular phenomena associated with C9orf72-ALS/FTD. In this review article, we will discuss the principles of phase separation, phase separation of the DPRs and repeat RNA themselves and how they perturb LLPS associated with membraneless organelles and the functional consequences of this. We will then discuss how phase separation may impact the major pathological feature of C9orf72-ALS/FTD, TDP-43 proteinopathy, and how LLPS may be targeted therapeutically in disease.

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