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Open Access 01-03-2019 | Amyotrophic Lateral Sclerosis | Original Paper

C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A

Authors: Thomas G. Moens, Teresa Niccoli, Katherine M. Wilson, Magda L. Atilano, Nicol Birsa, Lauren M. Gittings, Benedikt V. Holbling, Miranda C. Dyson, Annora Thoeng, Jacob Neeves, Idoia Glaria, Lu Yu, Julia Bussmann, Erik Storkebaum, Mercedes Pardo, Jyoti S. Choudhary, Pietro Fratta, Linda Partridge, Adrian M. Isaacs

Published in: Acta Neuropathologica | Issue 3/2019

Abstract

A GGGGCC hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense repeat-containing transcripts undergo repeat-associated non-AUG-initiated translation to produce five dipeptide proteins (DPRs). The polyGR and polyPR DPRs are extremely toxic when expressed in Drosophila neurons. To determine the mechanism that mediates this toxicity, we purified DPRs from the Drosophila brain and used mass spectrometry to identify the in vivo neuronal DPR interactome. PolyGR and polyPR interact with ribosomal proteins, and inhibit translation in both human iPSC-derived motor neurons, and adult Drosophila neurons. We next performed a screen of 81 translation-associated proteins in GGGGCC repeat-expressing Drosophila to determine whether this translational repression can be overcome and if this impacts neurodegeneration. Expression of the translation initiation factor eIF1A uniquely rescued DPR-induced toxicity in vivo, indicating that restoring translation is a potential therapeutic strategy. These data directly implicate translational repression in C9orf72 repeat-induced neurodegeneration and identify eIF1A as a novel modifier of C9orf72 repeat toxicity.

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Title: C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A
Authors: Thomas G. Moens
Teresa Niccoli
Katherine M. Wilson
Magda L. Atilano
Nicol Birsa
Lauren M. Gittings
Benedikt V. Holbling
Miranda C. Dyson
Annora Thoeng
Jacob Neeves
Idoia Glaria
Lu Yu
Julia Bussmann
Erik Storkebaum
Mercedes Pardo
Jyoti S. Choudhary
Pietro Fratta
Linda Partridge
Adrian M. Isaacs
Publication date: 01-03-2019
Publisher: Springer Berlin Heidelberg
Keywords: Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
Frontotemporal Dementia
Published in: Acta Neuropathologica / Issue 3/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1946-4

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C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A

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