APA
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Birsa, N., Ule, A., Garone, M. G., Tsang, B., Mattedi, F., Chong, P. A., … Fratta, P. (2020). FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation. Science Advances.
Chicago/Turabian
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Birsa, N., A. Ule, M. G. Garone, B. Tsang, F. Mattedi, P. A. Chong, J. Humphrey, et al. “FUS-ALS Mutants Alter FMRP Phase Separation Equilibrium and Impair Protein Translation.” Science Advances (2020).
MLA
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Birsa, N., et al. “FUS-ALS Mutants Alter FMRP Phase Separation Equilibrium and Impair Protein Translation.” Science Advances, 2020.
BibTeX Click to copy
@article{n2020a,
title = {FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation},
year = {2020},
journal = {Science Advances},
author = {Birsa, N. and Ule, A. and Garone, M. G. and Tsang, B. and Mattedi, F. and Chong, P. A. and Humphrey, J. and Jarvis, Seth and Pisiren, Melis and Wilkins, O. and Nosella, Michael L. and Devoy, A. and Bodo, C. and de la Fuente, Rafaela Fernandez and Fisher, E.M.C. and Rosa, A. and Viero, G. and Forman-Kay, J. and Schiavo, G. and Fratta, P.}
}
Cytoplasmic mislocalization of FUS-ALS mutants determines aberrant FMRP condensates and protein synthesis repression. 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.