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, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Teresa Niccoli, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Katherine M. Wilson, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Magda L. Atilano, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Nicol Birsa, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Lauren M. Gittings, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Benedikt V. Holbling, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Miranda C. Dyson, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Annora Thoeng, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Jacob Neeves, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Idoia Glaria, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Lu Yu, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Julia Bussmann, Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149, Münster, Germany.
Erik Storkebaum, Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149, Münster, Germany.
Mercedes Pardo, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Jyoti S. Choudhary, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Pietro Fratta, MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Linda Partridge, Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, Darwin Building, Gower Street, London, WC1E 6BT, UK. linda.partridge@ucl.ac.uk.
Adrian M. Isaacs, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. a.isaacs@ucl.ac.uk.

Document Type

Article

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.

Keywords

ALS, C9orf72, Dipeptide, Drosophila, FTD

Medical Subject Headings

Amyotrophic Lateral Sclerosis (genetics); Animals; Animals, Genetically Modified; Brain (metabolism); C9orf72 Protein (genetics, metabolism); DNA Repeat Expansion; Dipeptides (metabolism); Drosophila; Eukaryotic Initiation Factor-1 (metabolism); Frontotemporal Dementia (genetics); Humans; Neurons (metabolism); Protein Biosynthesis (physiology)

Publication Date

3-1-2019

Publication Title

Acta neuropathologica

E-ISSN

1432-0533

Volume

137

Issue

3

First Page

487

Last Page

500

PubMed ID

30604225

Digital Object Identifier (DOI)

10.1007/s00401-018-1946-4

Recommended Citation

Moens, Thomas G.; Niccoli, Teresa; Wilson, Katherine M.; Atilano, Magda L.; Birsa, Nicol; Gittings, Lauren M.; Holbling, Benedikt V.; Dyson, Miranda C.; Thoeng, Annora; Neeves, Jacob; Glaria, Idoia; Yu, Lu; Bussmann, Julia; Storkebaum, Erik; Pardo, Mercedes; Choudhary, Jyoti S.; Fratta, Pietro; Partridge, Linda; and Isaacs, Adrian M., "C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A" (2019). Translational Neuroscience. 2307.
https://scholar.barrowneuro.org/neurobiology/2307