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FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

Birsa, N; Ule, AM; Garone, MG; Tsang, B; Mattedi, F; Chong, PA; Humphrey, J; ... Fratta, P; + view all (2021) FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation. Science Advances , 7 (30) , Article eabf8660. 10.1126/sciadv.abf8660. Green open access

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Abstract

FUsed in Sarcoma (FUS) is a multifunctional RNA binding protein (RBP). FUS mutations lead to its cytoplasmic mislocalization and cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we use mouse and human models with endogenous ALS-associated mutations to study the early consequences of increased cytoplasmic FUS. We show that in axons, mutant FUS condensates sequester and promote the phase separation of fragile X mental retardation protein (FMRP), another RBP associated with neurodegeneration. This leads to repression of translation in mouse and human FUS-ALS motor neurons and is corroborated in vitro, where FUS and FMRP copartition and repress translation. Last, we show that translation of FMRP-bound RNAs is reduced in vivo in FUS-ALS motor neurons. Our results unravel new pathomechanisms of FUS-ALS and identify a novel paradigm by which mutations in one RBP favor the formation of condensates sequestering other RBPs, affecting crucial biological functions, such as protein translation.

Type: Article
Title: FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/sciadv.abf8660
Publisher version: http://doi.org/10.1126/sciadv.abf8660
Language: English
Additional information: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10131894
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