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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-symptomat...

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Autori principali: Saad, Céline (Autore) , Jung-Klawitter, Sabine (Autore) , Dimitrov, Bianca (Autore) , Aguilar-Pimentel, Juan Antonio (Autore) , Becker, Lore (Autore) , da Silva-Buttkus, Patricia (Autore) , Dragano, Nathalia R. V. (Autore) , Garrett, Lillian (Autore) , Hölter, Sabine M. (Autore) , Rathkolb, Birgit (Autore) , Sanz-Moreno, Adrián (Autore) , Spielmann, Nadine (Autore) , Fuchs, Helmut (Autore) , Gailus-Durner, Valerie (Autore) , Schaaf, Christian P. (Autore) , la Marca, Giancarlo (Autore) , Damiano, Roberta (Autore) , Lefeber, Dirk J. (Autore) , Engelke, Udo (Autore) , de Angelis, Martin Hrabe (Autore) , Houten, Sander M. (Autore) , Kölker, Stefan (Autore)
Natura: Article (Journal)
Lingua:inglese
Pubblicazione: 31 March 2026
In: Scientific reports
Year: 2026, Volume: 16, Fascicolo: 1, Pages: 1-18
ISSN:2045-2322
DOI:10.1038/s41598-026-44377-9
Accesso online:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41598-026-44377-9
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41598-026-44377-9
Testo
Note sull'autore: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, Martin Hrabe de Angelis, Sander M. Houten, Stefan Kölker
Descrizione
Riassunto: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.
Descrizione del documento:Gesehen am 10.08.2026
Online veröffentlicht: 31. März 2026
Descrizione fisica:Online Resource
ISSN:2045-2322
DOI:10.1038/s41598-026-44377-9

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