ArticleMolecular neurodegeneration2020
Premature termination codon readthrough upregulates progranulin expression and improves lysosomal function in preclinical models of GRN deficiency.
Article in Molecular neurodegeneration, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- Engineered tRNA reduces vision loss in a mouse model of Leber congenital amaurosis.Signal transduction and targeted therapy · 2026Article
- Recovery of α-L-fucosidase in fucosidosis nonsense variants by readthrough stimulation and release factor degradation.Disease models & mechanisms · 2026Article
- The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- High-fidelity and differential nonsense suppression in live cells and a frontotemporal dementia allele with human transfer RNAs.Nucleic acids research · 2025Article
- Review
- A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis.Journal of neuroinflammation · 2025Article
- Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells.Translational neurodegeneration · 2025Review
- A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis.Journal of clinical immunology · 2023Article
- Nonsense mutation suppression is enhanced by targeting different stages of the protein synthesis process.PLoS biology · 2023Article
- A NovelInternational journal of molecular sciences · 2023Article
- Amlexanox: Readthrough Induction and Nonsense-Mediated mRNA Decay Inhibition in a Charcot-Marie-Tooth Model of hiPSCs-Derived Neuronal Cells Harboring a Nonsense Mutation inPharmaceuticals (Basel, Switzerland) · 2023Article
- Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome.International journal of molecular sciences · 2023Article
- Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Review
- CRISPR-SCReT (CRISPR-Stop Codon Read Through) method to control Cas9 expression for gene editing.Gene therapy · 2022Article
- Small molecule Y-320 stimulates ribosome biogenesis, protein synthesis, and aminoglycoside-induced premature termination codon readthrough.PLoS biology · 2021Article
- Effect of small molecule eRF3 degraders on premature termination codon readthrough.Nucleic acids research · 2021Article
- Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities.Frontiers in molecular neuroscience · 2021Review
- Multiple Molecular Pathways Are Influenced by Progranulin in a Neuronal Cell Model-A Parallel Omics Approach.Frontiers in neuroscience · 2021Article
- Suppression of Nonsense Mutations by New Emerging Technologies.International journal of molecular sciences · 2020Review
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Authors and funding
17 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundFrontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.
methodsWe studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X
resultsThe R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X
conclusionsTaken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.
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