ArticlePLoS genetics2022
An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency.
Article in PLoS genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- An Unbiased Drug Screen in a Drosophila Model ofInternational journal of molecular sciences · 2026Article
- A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG.PLoS genetics · 2026Article
- A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG.bioRxiv : the preprint server for biology · 2026Article
- Transcriptomic data and biomedical literature synergize in finding pharmacologic gene regulators.bioRxiv : the preprint server for biology · 2026Article
- Cytosolic Peptide: N-Glycanase (NGLY1)-from Basic Biology to Genetic Disorder, NGLY1 Deficiency.Advances in experimental medicine and biology · 2026Review
- Modelling Neural Disorders with theBiomolecules · 2025Review
- Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity.PLoS genetics · 2025Article
- NGLY1 deficiency - clinical features and therapeutic strategy.Journal of human genetics · 2025Review
- A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.PLoS genetics · 2024Article
- Drosophila models of phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) mirror patient phenotypes.G3 (Bethesda, Md.) · 2024Article
- Strategies for dissecting the complexity of neurodevelopmental disorders.Trends in genetics : TIG · 2024Review
- Editorial: Community series in recent advances inFrontiers in immunology · 2024Article
- Exome/Genome Sequencing in Undiagnosed Syndromes.Annual review of medicine · 2023Review
- Generation and characterization of NGLY1 patient-derived midbrain organoids.Frontiers in cell and developmental biology · 2023Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in the N-glycanase 1 (NGLY1) gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used a Drosophila model of NGLY1 deficiency to conduct an in vivo, unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules partially rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. Exclusive dNGLY1 expression in serotonin and dopamine neurons, in an otherwise dNGLY1 deficient fly, was sufficient to partially rescue lethality. Further, genetic modifier and transcriptomic data supports the importance of serotonin signaling in NGLY1 deficiency. Connectivity Map analysis identified glycogen synthase kinase 3 (GSK3) inhibition as a potential therapeutic mechanism for NGLY1 deficiency, which we experimentally validated with TWS119, lithium, and GSK3 knockdown. Strikingly, GSK3 inhibitors and a serotonin modulator rescued size defects in dNGLY1 deficient larvae upon proteasome inhibition, suggesting that these compounds act through NRF1, a transcription factor that is regulated by NGLY1 and regulates proteasome expression. This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.
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