Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1
Year: 2026
Type: article
Abstract: Glutaric aciduria type 1 is caused by inherited deficiency of glutaryl-CoA dehydrogenase and subsequent accumulation of neurotoxic metabolites. Clinically, the disease is characterized by striatal damage and dystonic movement disorder in untreated infants. Despite newborn screening and pre-symptomatic therapy start, about one-third of patients still develop neurological symptoms. Furthermore, progressive white matter changes and chronic kidney disease highlights the need for improved therapies. To elucidate the potential of substrate reduction therapy for GA1 we investigated whether aminoadipate-semialdehyde synthetase, the first enzyme of the lysine oxidation pathway, could serve as therapeutic target. Therefore, we studied whether Gcdh knockout (KO) mice, a known animal model for GA1, were rescued by additional knockout of Aass. Gcdh/Aass KO mice were clinically indistinguishable from wild-type mice and showed a marked reduction of glutaric acid in brain (20.9 µg/mg protein vs. 59.2 µg/mg protein; p = 0.001), liver (23.5 µg/mg protein vs. 104.8 µg/mg protein; p = 0.001), and urine (11.9 mol/mol creatinine vs. 166.5 mol/mol creatinine; p = 0.001). The effect was less pronounced for 3-hydroxyglutaric acid. Unlike Gcdh KO mice, Gcdh/Aass KO mice did not develop a severe phenotype under high-lysine diet. In conclusion, knockout of Aass partially rescues the severe phenotype of Gcdh KO mice, providing a potential therapeutic target.
Source: Scientific Reports
Authors: Celine Saad, Sabine Jung-Klawitter, Bianca Dimitrov, Juan Antonio Aguilar-Pimentel, Lore Becker, Patricia da Silva-Buttkus, Nathalia R. V. Dragano, Lillian Garrett, Sabine M. Hölter, Birgit Rathkolb, Adrián Sanz-Moreno, Nadine Spielmann, Helmut Fuchs, Valerie Gailus-Durner, Christian P. Schaaf, Giancarlo la Marca, Roberta Damiano, Dirk J. Lefeber, Udo Engelke, Clara C. D. M. van Karnebeek, Alex Garanto Iglesias, Carole Linster, Curtis R. Coughlin, Blair R. Leavitt, Christina Fillat, Martin Hrabe de Angelis, Sander M. Houten, Stefan Kölker
Institutions: Heidelberg University, Helmholtz Munich, German Center for Diabetes Research, Ludwig-Maximilians-Universität München, Meyer Children's Hospital, University of Florence, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Amsterdam University Medical Centers, Amsterdam Gastroenterology Endocrinology Metabolism, Radboud Institute for Molecular Life Sciences, Amalia Kinderziekenhuis, University of Luxembourg, Luxembourg Centre for Systems Biomedicine, University of Colorado Anschutz, University of British Columbia, BC Children's Hospital Research Institute, Centre for Biomedical Network Research on Rare Diseases, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Technical University of Munich, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W7144098202