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Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in amyotrophic lateral sclerosis

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Item Type:Article
Title:Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in amyotrophic lateral sclerosis
Creators Name:De Santis, R. and Alfano, V. and de Turris, V. and Colantoni, A. and Santini, L. and Garone, M.G. and Antonacci, G. and Peruzzi, G. and Sudria-Lopez, E. and Wyler, E. and Anink, J.J. and Aronica, E. and Landthaler, M. and Pasterkamp, R.J. and Bozzoni, I. and Rosa, A.
Abstract:Amyotrophic lateral sclerosis (ALS) has been genetically linked to mutations in RNA-binding proteins (RBPs), including FUS. Here, we report the RNA interactome of wild-type and mutant FUS in human motor neurons (MNs). This analysis identified a number of RNA targets. Whereas the wild-type protein preferentially binds introns, the ALS mutation causes a shift toward 3′ UTRs. Neural ELAV-like RBPs are among mutant FUS targets. As a result, ELAVL4 protein levels are increased in mutant MNs. ELAVL4 and mutant FUS interact and co-localize in cytoplasmic speckles with altered biomechanical properties. Upon oxidative stress, ELAVL4 and mutant FUS are engaged in stress granules. In the spinal cord of FUS ALS patients, ELAVL4 represents a neural-specific component of FUS-positive cytoplasmic aggregates, whereas in sporadic patients it co-localizes with phosphorylated TDP-43-positive inclusions. We propose that pathological mutations in FUS trigger an aberrant crosstalk with ELAVL4 with implications for ALS.
Keywords:FUS, ELAVL4, HuD, Amytrophic Lateral Sclerosis, Motor Neuron, PAR-CLIP, TDP-43, Stress Granules, RNA-Binding Protein, Brillouin
Source:Cell Reports
ISSN:2211-1247
Publisher:Cell Press / Elsevier (U.S.A.)
Volume:27
Number:13
Page Range:3818-3831
Date:25 June 2019
Official Publication:https://doi.org/10.1016/j.celrep.2019.05.085
PubMed:View item in PubMed

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