ArticleThe EMBO journal2020
Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders.
Article in The EMBO journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers, 1 of them a synthesis that pooled it.
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Who cites it
99 citing papers in PubMed, 1 synthesis or guideline pooled it, 141 citations in OpenAlex.
- The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.Molecular neurobiology · 2025Pooled it
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Article
- Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.Neural regeneration research · 2026Article
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 2026Article
- Intrathecal (GActa neuropathologica communications · 2026Article
- Distinct cellular effects of myotonic dystrophy type 2 repeat-associated non-AUG tetrapeptides.Disease models & mechanisms · 2026Article
- Wild-typemedRxiv : the preprint server for health sciences · 2026Article
- C9orf72 hexanucleotide repeat expansions impair microglial response in ALS.Nature neuroscience · 2025Article
- Canonical translation factors eIF1A and eIF5B modulate the initiation step of repeat-associated non-AUG translation.Nucleic acids research · 2025Article
- Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.bioRxiv : the preprint server for biology · 2025Article
- Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.The Journal of clinical investigation · 2025Article
- Cryptic intronic transcriptional initiation generates efficient endogenous mRNA templates for C9orf72-associated RAN translation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Multi-modal comparative phenotyping of knock-in mouse models of frontotemporal dementia/amyotrophic lateral sclerosis.Disease models & mechanisms · 2025Article
- C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.Acta neuropathologica communications · 2025Article
- Genetic Basis of Motor Neuron Diseases: Insights, Clinical Management, and Future Directions.International journal of molecular sciences · 2025Review
- Article
- Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.Translational neurodegeneration · 2025Review
- Neuronal polyunsaturated fatty acids are protective in ALS/FTD.Nature neuroscience · 2025Article
- Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics.The Lancet. Neurology · 2025Review
39 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.