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2018

Hum Mol Genet 2018 Apr 1;27(7):1276-1289. doi: 10.1093/hmg/ddy043

Elongator subunit 3 (ELP3) modifies ALS through tRNA modification.

A Bento-Abreu;G Jager;B Swinnen;L Rué;S Hendrickx;A Jones;KA Staats;L Taes;C Eykens;A Nonneman;R Nuyts;M Timmers;L Silva;A Chariot;L Nguyen;J Ravits;R Lemmens;D Cabooter;L Van Den Bosch;P Van Damme;A Al-Chalabi;A Bystrom;W Robberecht

Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, B-3000 Leuven, Belgium. Laboratory of Neurobiology, VIB-Center for Brain & Disease Research, B-3000 Leuven, Belgium. Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden. Department of Neurology, University Hospitals Leuven, B-3000 Leuven, Belgium. Department of Pharmaceutical & Pharmacological Sciences, Pharmaceutical Analysis, B-3000 Leuven, Belgium. Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK. GIGA-Molecular Biology of Diseases and Walloon Excellence in Life Sciences and Biotechnology (WELBIO), C.H.U. Sart Tilman, B-4000 Liège, Belgium. GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, B-4000 Liège, Belgium. Department of Neurosciences, ALS Translational Research, University of California, San Diego, La Jolla, CA, USA.

Service type: Transgenic mice

Abstract

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.

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