ArticleActa neuropathologica2014
C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration.
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 211 papers, 1 of them a synthesis that pooled it.
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Who cites it
211 citing papers in PubMed, 1 synthesis or guideline pooled it, 324 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
- Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.bioRxiv : the preprint server for biology · 2026Article
- Engineered GM1 Intersects Between Mitochondrial and Synaptic Pathways to Ameliorate ALS Pathology.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration inInternational journal of molecular sciences · 2026Article
- Inhibition of PolyGA Dipeptide Repeat Protein Aggregation by Nucleic Acid Aptamers in C9 Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Models.Molecular neurobiology · 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
- Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: A bibliometric analysis.Medicine · 2025Article
- Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.Nature communications · 2025Article
- C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2024Article
- Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.Autophagy · 2024Article
- Pathological Involvement of Protein Phase Separation and Aggregation in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS/FTD phenotypes.EMBO reports · 2024Article
- Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.International journal of molecular sciences · 2024Review
- Proteotoxic stress and the ubiquitin proteasome system.Seminars in cell & developmental biology · 2024Review
- Neuropathogenesis-on-chips for neurodegenerative diseases.Nature communications · 2024Review
- Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo.Gene therapy · 2024Article
- ALS' Perfect Storm:Cells · 2024Review
151 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hexanucleotide repeat expansion in C9orf72 is the most common pathogenic mutation in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the lack of an ATG start codon, the repeat expansion is translated in all reading frames into dipeptide repeat (DPR) proteins, which form insoluble, ubiquitinated, p62-positive aggregates that are most abundant in the cerebral cortex and cerebellum. To specifically analyze DPR toxicity and aggregation, we expressed DPR proteins from synthetic genes containing a start codon but lacking extensive GGGGCC repeats. Poly-Gly-Ala (GA) formed p62-positive cytoplasmic aggregates, inhibited dendritic arborization and induced apoptosis in primary neurons. Quantitative mass spectrometry analysis to identify poly-GA co-aggregating proteins revealed a significant enrichment of proteins of the ubiquitin-proteasome system. Among the other interacting proteins, we identified the transport factor Unc119, which has been previously linked to neuromuscular and axonal function, as a poly-GA co-aggregating protein. Strikingly, the levels of soluble Unc119 are strongly reduced upon poly-GA expression in neurons, suggesting a loss of function mechanism. Similar to poly-GA expression, Unc119 knockdown inhibits dendritic branching and causes neurotoxicity. Unc119 overexpression partially rescues poly-GA toxicity suggesting that poly-GA expression causes Unc119 loss of function. In C9orf72 patients, Unc119 is detectable in 9.5 % of GA inclusions in the frontal cortex, but only in 1.6 % of GA inclusions in the cerebellum, an area largely spared of neurodegeneration. A fraction of neurons with Unc119 inclusions shows loss of cytosolic staining. Poly-GA-induced Unc119 loss of function may thereby contribute to selective vulnerability of neurons with DPR protein inclusions in the pathogenesis of C9orf72 FTLD/ALS.
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