Elongator subunit 3 (ELP3) modifies ALS through tRNA modification

ELP3 protein, zebrafish; Article; RNA processing; Amyotrophic Lateral Sclerosis; Animals; C9orf72 Protein; Histone Acetyltransferases; Motor Cortex; Nerve Tissue Proteins; RNA Processing, Post-Transcriptional; RNA, Transfer; Superoxide Dismutase-1; Zebrafish

Abstract :

[en] Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder of which the progression is influenced by several disease-modifying factors. Here, we investigated ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines, as one of such ALS disease modifiers. ELP3 attenuated the axonopathy of a mutant SOD1, as well as of a mutant C9orf72 ALS zebrafish model. Furthermore, the expression of ELP3 in the SOD1G93A mouse extended the survival and attenuated the denervation in this model. Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U and increased abundance of insoluble mutant SOD1, which was reverted by exogenous ELP3 expression. Interestingly, the expression of ELP3 in the motor cortex of ALS patients was reduced and correlated with mcm5s2U levels. Our results demonstrate that ELP3 is a modifier of ALS and suggest a link between tRNA modification and neurodegeneration. © The Author(s) 2018. Published by Oxford University Press. All rights reserved.

Disciplines :

Neurology

Author, co-author :

Bento-Abreu, A.; Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, B-3000, Belgium, Laboratory of Neurobiology, VIB-Center for Brain and Disease Research, Leuven, B-3000, Belgium

Jager, G.; Department of Molecular Biology, Umeå University, Umeå, 901 87, Sweden

Swinnen, B.; Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, B-3000, Belgium, Laboratory of Neurobiology, VIB-Center for Brain and Disease Research, Leuven, B-3000, Belgium, Department of Neurology, University Hospitals Leuven, Leuven, B-3000, Belgium

Rué, L.; Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, B-3000, Belgium, Laboratory of Neurobiology, VIB-Center for Brain and Disease Research, Leuven, B-3000, Belgium

Hendrickx, Sébastien ; Université de Liège - ULiège > Lepur(Centre rech.sur la Ville,le Territ.et le Milieu rural)

Jones, A.; Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, SE5 8AF, United Kingdom

Staats, K. A.; Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, B-3000, Belgium, Laboratory of Neurobiology, VIB-Center for Brain and Disease Research, Leuven, B-3000, Belgium

Taes, I.; Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, B-3000, Belgium, Laboratory of Neurobiology, VIB-Center for Brain and Disease Research, Leuven, B-3000, Belgium

Eykens, C.; Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, B-3000, Belgium, Laboratory of Neurobiology, VIB-Center for Brain and Disease Research, Leuven, B-3000, Belgium

Nonneman, A.; Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, B-3000, Belgium, Laboratory of Neurobiology, VIB-Center for Brain and Disease Research, Leuven, B-3000, Belgium

More authors (13 more)

Title :

Elongator subunit 3 (ELP3) modifies ALS through tRNA modification

Publication date :

2018

Journal title :

Human Molecular Genetics

ISSN :

0964-6906

eISSN :

1460-2083

Publisher :

Oxford University Press

Volume :

Issue :

Pages :

1276-1289

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 16 January 2020

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