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

Abstract

Mutations in the RNA binding protein (RBP) FUS cause amyotrophic lateral sclerosis (ALS) and result in its nuclear depletion and cytoplasmic mislocalisation, with cytoplasmic gain of function thought to be crucial in pathogenesis. Here, we show that expression of mutant FUS at physiological levels drives translation inhibition in both mouse and human motor neurons. Rather than acting directly on the translation machinery, we find that mutant FUS forms cytoplasmic condensates that promote the phase separation of FMRP, another RBP associated with neurodegeneration and robustly involved in translation regulation. FUS and FMRP co-partition and repress translation in vitro. In our in vivo model, FMRP RNA targets are depleted from ribosomes. Our results identify a novel paradigm by which FUS mutations favour the condensed state of other RBPs, impacting on crucial biological functions, such as protein translation.

Stress-induced perturbations in intracellular amino acids reprogram mRNA translation in osmoadaptation independently of the ISR

“…Further supporting a role of FUS in the biphasic translation program, we identified FUS-binding sites as enriched among mRNAs translationally repressed during the early phase and recovered during osmoadaptation (Figures S10E-S10F). Moreover, mRNAs whose translation was suppressed by MeAIB, but not torin 1, were enriched for FUS motifs (Figure S10G), consistent with previous studies showing that FUS mutants repress translation of a subset of mRNAs in neurons (Birsa et al, 2021). Collectively, these findings suggest that FUS likely plays a role in SNAT2-dependent translation reprograming during mild hyperosmotic stress.…”

Axonal Length Determines Distinct Homeostatic Phenotypes in Human iPSC Derived Motor Neurons on a Bioengineered Platform

“…To maintain and regulate both translation and RNA metabolism within the axon, a number of RNA binding proteins (RBPs) are localized within the axon, [ 41 ] coordinating transport, granule formation and delivery of the mRNA to sites of local protein translation, [ 42 ] subsequently influencing the production rate of proteins at these sides. [ 43 ] Moreover, RBPs exhibit a broad influence on RNA splicing, stability, and transcription, wherefore it is not surprising that their malfunction makes them key player in neurodegenerative diseases. [ 18,22,44 ] We focused on two of these key RBPs, fused in sarcoma (FUS) and transactive DNA response binding protein 43 (TDP‐43), as they are required in the healthy axon and are known to cause ALS.…”

Walking the line: mechanisms underlying directional mRNA transport and localisation in neurons and beyond

“…Defects in RNA processing such as translation, splicing and transport have been documented in several neurodegenerative disorders such as, ALS, frontotemporal dementia (FTD) and Huntington's disease [ 125 , 126 ]. A prominent feature of such disorders is the formation of nuclear and cytoplasmic RNP aggregates; for instance, TDP-43 aggregates are commonly observed in ALS and FTD regardless of the underlying genetic cause [ 125 , 127 , 128 ]. These aggregates could further impair RNA processing by sequestering RNAs and RBPs, thus preventing them from carrying out their functions.…”