Elongator Subunit 3 (ELP3) Modifies ALS Through TRNA Modification

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2018 Feb 8

PMID 29415125

Citations 36

Authors

Andre Bento-Abreu

Gunilla Jager

Bart Swinnen

Laura Rue

Stijn Hendrickx

Ashley Jones

Kim A Staats

Ines Taes

Caroline Eykens

Annelies Nonneman

Rik Nuyts

Mieke Timmers

Lara Silva

Alain Chariot

Laurent Nguyen

John Ravits

Robin Lemmens

Deirdre Cabooter

Ludo Van Den Bosch

Philip Van Damme

Ammar Al-Chalabi

Anders Bystrom

Wim Robberecht

Affiliations

Soon will be listed here.

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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