ArticleHuman molecular genetics2017
Nuclear localized C9orf72-associated arginine-containing dipeptides exhibit age-dependent toxicity in C. elegans.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 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
- Hexavalent chromium neurotoxicity in Caenorhabditis elegans targeted GABAergic, cholinergic, and dopaminergic neurons, and contributed to an aged phenotype.Neurotoxicology · 2025Article
- A Brief Review on Caenorhabditis elegans Role in Modelling Neurodegenerative Disease.Central nervous system agents in medicinal chemistry · 2025Review
- Review
- Towards Understanding Neurodegenerative Diseases: Insights fromInternational journal of molecular sciences · 2023Review
- Article
- Translation of dipeptide repeat proteins ineLife · 2023Article
- FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA ineLife · 2023Article
- Review
- Simple models to understand complex disease: 10 years of progress fromFrontiers in neuroscience · 2023Review
- Protein clearance strategies for disease intervention.Journal of neural transmission (Vienna, Austria : 1996) · 2022Review
- Length-dependent RNA foci formation and Repeat Associated non-AUG dependent translation in amicroPublication biology · 2022Article
- Review
- Charcot-Marie-tooth disease causing mutation (p.R158H) in pyruvate dehydrogenase kinase 3 (PDK3) affects synaptic transmission, ATP production and causes neurodegeneration in a CMTX6 C. elegans model.Human molecular genetics · 2021Article
- A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation.Nature communications · 2021Article
- The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Measuring and Interpreting Nuclear Transport in Neurodegenerative Disease-The Example of C9orf72 ALS.International journal of molecular sciences · 2021Review
- Modeling neurodegeneration inDisease models & mechanisms · 2020Review
- Article
- Divergence, Convergence, and Therapeutic Implications: A Cell Biology Perspective of C9ORF72-ALS/FTD.Molecular neurodegeneration · 2020Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
A hexanucleotide repeat expansion mutation in the C9orf72 gene represents a prevalent genetic cause of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Non-canonical translation of this repeat gives rise to several distinct dipeptide protein species that could play pathological roles in disease. Here, we show in the model system Caenorhabditis elegans that expression of the arginine-containing dipeptides, but not alanine-containing dipeptides, produces toxic phenotypes in multiple cellular contexts, including motor neurons. Expression of either (PR)50 or (GR)50 during development caused a highly penetrant developmental arrest, while post-developmental expression caused age-onset paralysis. Both (PR)50- and (GR)50-green fluorescent protein tagged dipeptides were present in the nucleus and nuclear localization was necessary and sufficient for their toxicity. Using an inducible expression system, we discovered that age-onset phenotypes caused by (PR)50 required both continual (PR)50 expression and an aged cellular environment. The toxicity of (PR)50 was modified by genetic mutations that uncouple physiological aging from chronological aging. However, these same mutations failed to modify the toxicity of (GR)50, suggesting that (PR)50 and (GR)50 exert their toxicity through partially distinct mechanism(s). Changing the rate of physiological aging also mitigates toxicity in other C. elegans models of ALS, suggesting that the (PR)50 dipeptide might engage similar toxicity mechanisms as other ALS disease-causing proteins.
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