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

55 Pages Posted: 8 Oct 2018 Publication Status: Published

See all articles by Riccardo De Santis

Riccardo De Santis

Istituto Italiano di Tecnologia - Center for Life Nano Science

Vincenzo Alfano

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Valeria de Turris

Istituto Italiano di Tecnologia - Center for Life Nano Science

Alessio Colantoni

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Laura Santini

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Maria Giovanna Garone

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Giuseppe Antonacci

Istituto Italiano di Tecnologia - Center for Life Nano Science

Giovanna Peruzzi

Istituto Italiano di Tecnologia - Center for Life Nano Science

Emma Sudria-Lopez

Utrecht University - Department of Translational Neuroscience

Emanuel Wyler

Helmholtz Association of German Research Centres - Berlin Institute for Medical Systems Biology

Jasper J. Anink

University of Amsterdam - Department of Neuropathology

Eleonora Aronica

University of Amsterdam, Academic Medical Center, Department of (Neuro)Pathology

Markus Landthaler

Helmholtz Association of German Research Centres - Berlin Institute for Medical Systems Biology

R. Jeroen Pasterkamp

Utrecht University - Department of Translational Neuroscience

Irene Bozzoni

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Alessandro Rosa

Istituto Italiano di Tecnologia - Center for Life Nano Science

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Abstract

The motor neuron disease 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 induced Pluripotent Stem Cells (iPSC)-derived motor neurons (MNs). We show that, whereas the wild-type protein preferentially binds introns, the ALS mutation causes a shift towards 3’ untranslated regions (3’UTRs). The neural specific 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 ALS patients ELAVL4 represents a neural specific component of FUS-positive cytoplasmic aggregates. We propose that pathological mutations in FUS trigger an aberrant crosstalk with ELAVL4 with implications for ALS.

Suggested Citation

De Santis, Riccardo and Alfano, Vincenzo and de Turris, Valeria and Colantoni, Alessio and Santini, Laura and Garone, Maria Giovanna and Antonacci, Giuseppe and Peruzzi, Giovanna and Sudria-Lopez, Emma and Wyler, Emanuel and Anink, Jasper J. and Aronica, Eleonora and Landthaler, Markus and Pasterkamp, R. Jeroen and Bozzoni, Irene and Rosa, Alessandro, Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis (October 6, 2018). Available at SSRN: https://ssrn.com/abstract=3261820 or http://dx.doi.org/10.2139/ssrn.3261820
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Riccardo De Santis

Istituto Italiano di Tecnologia - Center for Life Nano Science

Viale Regina Elena 291
Rome, 00161
Italy

Vincenzo Alfano

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Piazzale Aldo Moro, 5
Rome, 00185
Italy

Valeria De Turris

Istituto Italiano di Tecnologia - Center for Life Nano Science

Viale Regina Elena 291
Rome, 00161
Italy

Alessio Colantoni

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Piazzale Aldo Moro, 5
Rome, 00185
Italy

Laura Santini

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Piazzale Aldo Moro, 5
Rome, 00185
Italy

Maria Giovanna Garone

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Piazzale Aldo Moro, 5
Rome, 00185
Italy

Giuseppe Antonacci

Istituto Italiano di Tecnologia - Center for Life Nano Science

Viale Regina Elena 291
Rome, 00161
Italy

Giovanna Peruzzi

Istituto Italiano di Tecnologia - Center for Life Nano Science

Viale Regina Elena 291
Rome, 00161
Italy

Emma Sudria-Lopez

Utrecht University - Department of Translational Neuroscience

Utrecht
Netherlands

Emanuel Wyler

Helmholtz Association of German Research Centres - Berlin Institute for Medical Systems Biology

Anna-Louisa-Karsch-Straße 2
Robert-Rössle-Str. 10
Berlin, Berlin 10178
United States

Jasper J. Anink

University of Amsterdam - Department of Neuropathology

Spui 21
Amsterdam, 1018 WB
Netherlands

Eleonora Aronica

University of Amsterdam, Academic Medical Center, Department of (Neuro)Pathology

Netherlands

Markus Landthaler

Helmholtz Association of German Research Centres - Berlin Institute for Medical Systems Biology

Anna-Louisa-Karsch-Straße 2
Robert-Rössle-Str. 10
Berlin, Berlin 10178
United States

R. Jeroen Pasterkamp

Utrecht University - Department of Translational Neuroscience

Utrecht
Netherlands

Irene Bozzoni

University of Rome I - Department of Biology and Biotechnology Charles Darwin (BBCD)

Piazzale Aldo Moro, 5
Rome, 00185
Italy

Alessandro Rosa (Contact Author)

Istituto Italiano di Tecnologia - Center for Life Nano Science ( email )

Viale Regina Elena 291
Rome, 00161
Italy

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