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Abstract

Glutaric aciduria type 1 (GA1) (OMIM #231670) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in the GCDH gene (19p13.13). Deficiency of glutaryl-CoA dehydrogenase (GCDH) results in accumulation of neurotoxic glutaryl-CoA, glutaric acid, and 3-hydroxyglutaric acid. Clinically, GA1 features acute or insidious striatal damage causing variable movement disorders in infancy. Despite early diagnosis and treatment, current therapies remain suboptimal, and many patients develop dystonia, white-matter changes, intellectual impairment, and chronic kidney disease. This study aimed to identify a target for substrate reduction therapy (SRT) focusing on lysine-degradation enzymes upstream of GCDH and to develop a human iPSC-based GA1 model. In vivo experiments used a Gcdh KO mouse combined with Aass or Aadat knockouts. All groups experienced metabolic stress using a high-lysine diet (HLD) to provoke the GA1 phenotype. Behavioral, histological, and biochemical assessments evaluated neuropathological and systemic alterations. Analysis of Gcdh/Aadat KO and Gcdh/Aass KO mice showed that Aadat deletion did not ameliorate disease symptoms. Although neurotoxin reductions were seen in Gcdh/Aadat KO brains, this improvement was tissue-restricted, suggesting limited therapeutic coverage. Consistently, pharmacological AADAT inhibition with PF-04859989 had no benefit, demonstrating that AADAT is not a suitable monotherapy target. In contrast, Aass deletion provided systemic protection: Gcdh/Aass KO mice exhibited markedly reduced neurotoxins, attenuated neurological impairment, and improved overall condition under HLD stress. These findings indicate that blocking lysine metabolism effectively prevents neurotoxic metabolite formation. Taken together, the findings support AASS inhibition or knockout as a promising SRT strategy for GA1, demonstrating metabolic and phenotypic benefits in preclinical models and providing a foundation for more effective therapies.