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

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.

• Authors: Nicol Birsa, Agnieszka M Ule, Maria Giovanna Garone, Brian Tsang, Francesca Mattedi, P Andrew Chong, Jack Humphrey, Seth Jarvis, Melis Pisiren, Oscar G Wilkins, Micheal L Nosella, Anny Devoy, Cristian Bodo, Rafaela Fernandez de la Fuente, Elizabeth M C Fisher, Alessandro Rosa, Gabriella Viero, Julie D Forman-Kay, Giampietro Schiavo, Pietro Fratta
• Journal: Science advances (Sci Adv) Vol. 7 Issue 30 (07 2021) ISSN: 2375-2548 [Electronic] United States
• PMID: 34290090 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 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).

Chemical References

• RNA-Binding Protein FUS
• Fragile X Mental Retardation Protein

Topics

• Amyotrophic Lateral Sclerosis (genetics)
• Animals
• Fragile X Mental Retardation Protein (genetics)
• Mice
• Mutation
• Neurodegenerative Diseases
• Protein Biosynthesis
• RNA-Binding Protein FUS (genetics)