ArticleActa neuropathologica2014
Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress.
Article in Acta neuropathologica, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 220 papers, 1 of them a synthesis that pooled it.
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Who cites it
220 citing papers in PubMed, 1 synthesis or guideline pooled it, 338 citations in OpenAlex.
- Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis.Cerebellum (London, England) · 2022Pooled it
- Two dipeptide repeat proteins are produced from mammalian telomeric RNA previously thought to be a long non-coding RNA.RNA biology · 2026Review
- Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.Nucleic acids research · 2026Article
- RAN Translation-Coupled Decay of theInternational journal of molecular sciences · 2026Article
- Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.bioRxiv : the preprint server for biology · 2026Article
- Designing polymer-peptide conjugates to target dipeptide repeat aggregates implicated in amyotrophic lateral sclerosis.Journal of materials chemistry. B · 2026Article
- Intrathecal (GActa neuropathologica communications · 2026Article
- A framework for the exploration of subcellular compartmentalization of RNA-binding proteins.Nature communications · 2026Article
- Engineered GM1 Intersects Between Mitochondrial and Synaptic Pathways to Ameliorate ALS Pathology.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Intrathecal (GbioRxiv : the preprint server for biology · 2026Article
- Inhibiting Glycogen Synthase Kinase 3 Suppresses TDP-43-Mediated Neurotoxicity in a Caspase-Dependent Manner.Molecular neurobiology · 2026Article
- Article
- Nucleolar aggregation of key neuropathological proteins in the postmortem neurodegenerative brain.Acta neuropathologica · 2025Article
- The Ubiquitin-Proteasome System in Brain Disorders: Pathogenic Pathways, Post-Translational Tweaks, and Therapeutic Frontiers.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Review
- Article
- 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
- Selenium Nanoparticles as Neuroprotective Agents: Insights into Molecular Mechanisms for Parkinson's Disease Treatment.Molecular neurobiology · 2025Review
- Targeting GeneInternational journal of molecular sciences · 2025Review
- Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Studying C9orf72 dipeptide repeat polypeptide aggregation using an analytical ultracentrifuge equipped with fluorescence detection.Analytical biochemistry · 2025Article
160 more citing papers are in PubMed but not listed here.
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Authors and funding
22 authors at 4 institutions in 1 country.
Funding
Abstract
The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the "c9RAN proteins" thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.
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