ArticleGene therapy2024
Modeling Glutaric Aciduria Type I in human neuroblastoma cells recapitulates neuronal damage that can be rescued by gene replacement.
Article in Gene therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 5 citations in OpenAlex.
- Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1.Scientific reports · 2026Article
- Untargeted LC-HRMS of Dried Blood Spots Reveals Metabolic Alterations and Candidate Biomarkers in Glutaric Aciduria Type-1.Metabolites · 2026Article
- Integrative multiomics elucidate crotonylation-associated GCDH in Parkinson's disease pathogenesis via metabolome remodeling.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- A Genetically Encoded Biosensor for Characterizing Transport and Metabolism of Glutarate.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model.Molecular therapy. Methods & clinical development · 2024Article
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glutaric Aciduria type I (GA1) is a rare neurometabolic disorder caused by mutations in the GDCH gene encoding for glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine and tryptophan. GCDH deficiency leads to increased concentrations of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body fluids and tissues. These metabolites are the main triggers of brain damage. Mechanistic studies supporting neurotoxicity in mouse models have been conducted. However, the different vulnerability to some stressors between mouse and human brain cells reveals the need to have a reliable human neuronal model to study GA1 pathogenesis. In the present work we generated a GCDH knockout (KO) in the human neuroblastoma cell line SH-SY5Y by CRISPR/Cas9 technology. SH-SY5Y-GCDH KO cells accumulate GA, 3-OHGA, and glutarylcarnitine when exposed to lysine overload. GA or lysine treatment triggered neuronal damage in GCDH deficient cells. SH-SY5Y-GCDH KO cells also displayed features of GA1 pathogenesis such as increased oxidative stress vulnerability. Restoration of the GCDH activity by gene replacement rescued neuronal alterations. Thus, our findings provide a human neuronal cellular model of GA1 to study this disease and show the potential of gene therapy to rescue GCDH deficiency.
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