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Saad, C.* ; Jung-Klawitter, S.* ; Dimitrov, B.* ; Aguilar-Pimentel, J.A. ; Becker, L. ; da Silva Buttkus, P. ; Dragano, N.R.V. ; Garrett, L. ; Hölter, S.M. ; Rathkolb, B. ; Sanz-Moreno, A. ; Spielmann, N. ; Fuchs, H. ; Gailus-Durner, V. ; Schaaf, C.P.* ; la Marca, G.* ; Damiano, R.* ; Lefeber, D.J.* ; Engelke, U.* ; Hrabě de Angelis, M. ; Houten, S.M.* ; Kölker, S.*

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

Sci. Rep. 16:10995 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Aminoadipate-semialdehyde Synthetase ; Glutaric Acid ; Glutaric Aciduria Type 1 ; Glutaryl-coa Dehydrogenase; Coenzyme-a Dehydrogenase; Blood-brain-barrier; Lysine Metabolism; Natural-history; Neurodegeneration; Susceptibility; Identification; Bioenergetics; Modulation; Efficacy
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Zeitschrift Scientific Reports
Quellenangaben Band: 16, Heft: 1, Seiten: , Artikelnummer: 10995 Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Förderungen Medizinische Fakultt Heidelberg der Universitt Heidelberg (9149)