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

• Published in: Acta neuropathologica 2019-03, Vol.137 (3), p.487-500
• Main Authors: 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, Isaacs, Adrian M.
• Format: Article
• Language: English
• Subjects: Amino acids; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animals; Animals, Genetically Modified; Antisense therapy; Arginine; Brain - metabolism; C9orf72 Protein - genetics; C9orf72 Protein - metabolism; Dementia disorders; Dipeptides - metabolism; DNA Repeat Expansion; Drosophila; EDTA; Eukaryotic Initiation Factor-1 - metabolism; Frontotemporal dementia; Frontotemporal Dementia - genetics; Genes; Genetic aspects; Humans; Insects; Mass spectrometry; Mass spectroscopy; Medicine; Medicine & Public Health; Motor neurons; Neurodegeneration; Neurons; Neurons - metabolism; Neurophysiology; Neurosciences; Novels; Original Paper; Pathology; Protein Biosynthesis - physiology; Proteins; Ribosomal proteins; Spectroscopy; Toxicity; Translation; Translation (Genetics)
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-018-1946-4

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.