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Cell Rep. 2019 Jun 25;27(13):3818-3831.e5. doi: 10.1016/j.celrep.2019.05.085.

Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis.

Author information

1
Center for Life Nano Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy; Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
2
Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
3
Center for Life Nano Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.
4
Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
5
Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
6
Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
7
Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Strasse 10, 13125 Berlin, Germany; IRI Life Sciences, Institute für Biologie, Humboldt Universität zu Berlin, Philippstraße 13, 10115 Berlin, Germany.
8
Center for Life Nano Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy; Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: alessandro.rosa@uniroma1.it.

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:

Brillouin; ELAVL4; FUS; HuD; PAR-CLIP; RNA-binding protein; TDP-43; amytrophic lateral sclerosis; motor neuron; stress granules

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