ArticleNature neuroscience2020
Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72.
Article in Nature neuroscience, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 159 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
159 citing papers in PubMed, 1 synthesis or guideline pooled it, 233 citations in OpenAlex.
- The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.Molecular neurobiology · 2025Pooled it
- Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers.European journal of neurology · 2026Article
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 2026Article
- Intrathecal (GActa neuropathologica communications · 2026Article
- Transcription and cohesin direct domain boundary spatial positioning and are linked to Friedreich's ataxia.Molecular cell · 2026Article
- C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen.Cell reports · 2026Article
- Intrathecal (GbioRxiv : the preprint server for biology · 2026Article
- Wild-typemedRxiv : the preprint server for health sciences · 2026Article
- Blocking RAN translation without altering repeat RNAs rescuesScience (New York, N.Y.) · 2026Article
- Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.Frontiers in pharmacology · 2026Review
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- Article
- Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.Journal of neuroinflammation · 2025Article
- Article
- Review
- C9orf72 hexanucleotide repeat expansions impair microglial response in ALS.Nature neuroscience · 2025Article
- Inhibition of PolyGA Dipeptide Repeat Protein Aggregation by Nucleic Acid Aptamers in C9 Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Models.Molecular neurobiology · 2025Article
- Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.bioRxiv : the preprint server for biology · 2025Article
- C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.Acta neuropathologica communications · 2025Article
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
99 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 8 institutions in 3 countries.
Funding
Abstract
Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of 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.