Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders. (13th January 2020)

• Record Type: Journal Article
• Authors: Boivin, Manon; Pfister, Véronique; Gaucherot, Angeline; Ruffenach, Frank; Negroni, Luc; Sellier, Chantal; Charlet‐Berguerand, Nicolas
• Is Part Of: EMBO journal. Volume 39:Number 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-01-13
• Subjects: amyotrophic lateral sclerosis -- autophagy -- C9ORF72 -- neurodegeneration -- RAN translation; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018100574
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Expansion of G4C2 repeats within the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Such repeats lead to decreased expression of the autophagy regulator C9ORF72 protein. Furthermore, sense and antisense repeats are translated into toxic dipeptide repeat (DPR) proteins. It is unclear how these repeats are translated, and in which way their translation and the reduced expression of C9ORF72 modulate repeat toxicity. Here, we found that sense and antisense repeats are translated upon initiation at canonical AUG or near‐cognate start codons, resulting in polyGA‐, polyPG‐, and to a lesser degree polyGR‐DPR proteins. However, accumulation of these proteins is prevented by autophagy. Importantly, reduced C9ORF72 levels lead to suboptimal autophagy, thereby impairing clearance of DPR proteins and causing their toxic accumulation, ultimately resulting in neuronal cell death. Of clinical importance, pharmacological compounds activating autophagy can prevent neuronal cell death caused by DPR proteins accumulation. These results suggest the existence of a double‐hit pathogenic mechanism in ALS/FTD, whereby reduced expression of C9ORF72 synergizes with DPR protein accumulation and toxicity. Synopsis: An expansion of G4C2 repeats in the C9ORF72 gene causes amyotrophic lateral sclerosis (ALS). Here, cell transfection and mass spectrometry indicate that G4C2 repeats are translated through classical initiation to cognate ATG or near‐cognate start codons. Furthermore, impaired autophagy due to reduced expression of the C9ORF72 protein synergizes toxicity of G4C2 translation. Sense G4C2 repeats are translated into polyGA and polyGR‐containing proteins, which initiate at a CUG and an AGG near‐cognate codon, respectively. Antisense C4G2 repeats are translated into a polyPG‐containing protein that initiates at an ATG start codon. Loss of C9ORF72 protein impairs autophagy, which promotes the accumulation and thus the toxicity of polyGA, polyPG and polyGR proteins. Abstract : ALS‐linked sense and antisense repeats are translated into toxic peptides that require clearance by C9ORF72‐dependent autophagy.