Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1

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.

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Journal
Scientific Reports
Published
2026-03-31
DOI
https://doi.org/10.1038/s41598-026-44377-9
Primary Topic
Metabolism and Genetic Disorders
Type
article
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0.00

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article

Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1

Martin Hrabě de Angelis, Birgit Rathkolb, Sander M. Houten, Giancarlo la Marca et al.
Scientific Reports
Metabolism and Genetic Disorders
article

Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1

Martin Hrabě de Angelis, Birgit Rathkolb, Sander M. Houten, Giancarlo la Marca, Roberta Damiano, Sabine M. Hölter, Blair R. Leavitt, Bianca Dimitrov, Lore Becker, Nadine Spielmann, Lillian Garrett, Curtis R. Coughlin, Dirk J. Lefeber, Juan Antonio Aguilar-Pimentel, Patricia da Silva-Buttkus, Celine Saad, Carole Linster, Nathalia R. V. Dragano, Christina Fillat, Sabine Jung-Klawitter, Stefan Kölker, Clara C. D. M. van Karnebeek, Helmut Fuchs, Udo Engelke, Christian P. Schaaf, Alex Garanto Iglesias, Valerie Gailus-Durner, Adrián Sanz-Moreno
article en

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.

Scientific ReportsVol. 16(1)
University of British Columbia (CA), Radboud University Nijmegen (NL), University of Luxembourg (LU), Heidelberg University (DE), University Hospital Heidelberg (DE), Radboud University Medical Center (NL), Helmholtz Zentrum München (DE), Departament de Salut (ES), Radboud Institute for Molecular Life Sciences (NL), Centre for Biomedical Network Research on Rare Diseases (ES), Meyer Children's Hospital (IT), Amalia Kinderziekenhuis (NL), Centro de Investigación Biomédica en Red (ES), Amsterdam University Medical Centers (NL), Deutsches Diabetes-Zentrum e.V. (DE), BC Children's Hospital (CA), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), German Center for Diabetes Research (DE), Heinrich Heine University Düsseldorf (DE), University of Florence (IT), University of Colorado Anschutz Medical Campus (US), Technical University of Munich (DE), Universitat de Barcelona (ES), Ludwig-Maximilians-Universität München (DE), Icahn School of Medicine at Mount Sinai (US)
European Commission, Deutsche Forschungsgemeinschaft
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