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Cited by 70Amyotrophic Lateral Sclerosis ResearchRNA Research and SplicingHereditary Neurological Disorders

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

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De Santis, Riccardo, Alfano, Vincenzo, de Turris, Valeria, Colantoni, Alessio, Santini, Laura, Garone, Maria Giovanna, Antonacci, Giuseppe, Peruzzi, Giovanna +8 more·2019·Cell Reports
DOI 10.1016/j.celrep.2019.05.085PMC PMC6613039
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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.

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Authors
De Santis, R., Alfano, V., de Turris, V., Colantoni, A., Santini, L., Garone, M. G., Antonacci, G., Peruzzi, G., Sudria-Lopez, E., Wyler, E., Anink, J. J., Aronica, E., Landthaler, M., Pasterkamp, R. J., Bozzoni, I., & Rosa, A.
Affiliations
  • Sapienza University of Rome (IT)
  • Italian Institute of Technology (IT)
  • Max Delbrück Center (DE)
  • Amsterdam Neuroscience (NL)
  • Utrecht University (NL)
Corresponding author
Rosa, Alessandro
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-06
Volume
27
Issue
13
Pages
3818-3831.e5
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2019.05.085
PMC
PMC6613039
OpenAlex
W2955147361
Cited by
70
References
66
Citations by year
2026: 8 · 2025: 8 · 2024: 8 · 2023: 8 · 2022: 10 · 2021: 14 · 2020: 12 · 2019: 2
FWCI
4.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • SSRN Electronic Journal (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc-sa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica (ERC-2013, AdG 340172)
  • Fondazione Telethon (GGP16213)
  • Prinses Beatrix Spierfonds
  • National Cancer Institute
  • National Institute on Drug Abuse
  • National Heart, Lung, and Blood Institute
  • Human Frontier Science Program (RGP0009/2014)
  • National Human Genome Research Institute
  • National Institute of Neurological Disorders and Stroke
  • National Institutes of Health
  • Istituto Italiano di Tecnologia
  • National Institute of Mental Health
  • European Research Council
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
amyotrophic lateral sclerosis, FUS, ELAVL4, HUD, RNA-binding proteins, RNA interactome, motor neurons, 3' UTR binding, stress granules, oxidative stress, cytoplasmic aggregates, TDP-43, protein-protein interaction
MeSH terms
ELAV-Like Protein 4, Amyotrophic Lateral Sclerosis, Cytoplasm, DNA-Binding Proteins, Humans, Mutation, Oxidative Stress, 3' Untranslated Regions, RNA-Binding Protein FUS, Induced Pluripotent Stem Cells

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