ArticleHuman molecular genetics2017
C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten.
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 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage.Molecular psychiatry · 2026Article
- Digital color-coded molecular barcoding reveals dysregulation of common FUS and FMRP targets in soma and neurites of ALS mutant motoneurons.Cell death discovery · 2023Article
- Review
- Dipeptide Repeat Pathology inAntioxidants (Basel, Switzerland) · 2022Article
- NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility.Nature communications · 2022Article
- Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology.Nature neuroscience · 2021Article
- Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis.Molecular brain · 2021Article
- The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis.Journal of personalized medicine · 2021Review
- Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides.The EMBO journal · 2021Article
- Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity ineLife · 2021Article
- RNA-mediated toxicity in C9orf72 ALS and FTD.Neurobiology of disease · 2020Review
- RNA toxicity in non-coding repeat expansion disorders.The EMBO journal · 2020Review
- Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway.Acta neuropathologica communications · 2019Article
- Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease.Annual review of neuroscience · 2019Review
- C9orf72-mediated ALS and FTD: multiple pathways to disease.Nature reviews. Neurology · 2018Review
- The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia.Human molecular genetics · 2018Article
- Viral delivery ofDisease models & mechanisms · 2017Article
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Authors and funding
16 authors at 3 institutions in 3 countries.
Funding
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease, characterised by progressive failure of the neuromuscular system. A (G4C2)n repeat expansion in C9ORF72 is the most common genetic cause of ALS and frontotemporal dementia (FTD). To date, the balance of evidence indicates that the (G4C2)n repeat causes toxicity and neurodegeneration via a gain-of-toxic function mechanism; either through direct RNA toxicity or through the production of toxic aggregating dipeptide repeat proteins. Here, we have generated a stable and isogenic motor neuronal NSC34 cell model with inducible expression of a (G4C2)102 repeat, to investigate the gain-of-toxic function mechanisms. The expression of the (G4C2)102 repeat produces RNA foci and also undergoes RAN translation. In addition, the expression of the (G4C2)102 repeat shows cellular toxicity. Through comparison of transcriptomic data from the cellular model with laser-captured spinal motor neurons from C9ORF72-ALS cases, we also demonstrate that the PI3K/Akt cell survival signalling pathway is dysregulated in both systems. Furthermore, partial knockdown of Pten rescues the toxicity observed in the NSC34 (G4C2)102 cellular gain-of-toxic function model of C9ORF72-ALS. Our data indicate that PTEN may provide a potential therapeutic target to ameliorate toxic effects of the (G4C2)n repeat.
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