Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease
López Blanco, José Manuel (Universitat Autònoma de Barcelona. Institut de Neurociències)
Outtrim, Esther L. (Emory University School of Medicine)
Fu, Rong (Emory University School of Medicine)
Sutcliffe, Diane J. (Emory University School of Medicine)
Torres, Rosa J. (Hospital Universitario La Paz (Madrid))
Jinnah, H. A. (Emory University School of Medicine)
Universitat Autònoma de Barcelona. Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular

Data:	2020
Descripció:	9 pàg.
Resum:	Lesch-Nyhan disease (LND), caused by a deficient salvage purine pathway, is characterized by severe neurological manifestations and uric acid overproduction. However, uric acid is not responsible for brain dysfunction, and it has been suggested that purine nucleotide depletion, or accumulation of other toxic purine intermediates, could be more relevant. Here we show that purine alterations in LND fibroblasts depend on the level of folic acid in the culture media. Thus, physiological levels of folic acid induce accumulation of 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediary of de novo purine biosynthetic pathway, and depletion of ATP. Additionally, Z-nucleotide derivatives (AICAr, AICA) are detected at high levels in the urine of patients with LND and its variants (hypoxanthine-guanine phosphoribosyltransferase [HGprt]-related neurological dysfunction and HGprt-related hyperuricemia), and the ratio of AICAr/AICA is significantly increased in patients with neurological problems (LND and HGprt-related neurological dysfunction). Moreover, AICAr is present in the cerebrospinal fluid of patients with LND, but not in control individuals. We hypothesize that purine alterations detected in LND fibroblasts may also occur in the brain of patients with LND.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	AICAr ; Folic acid ; Lesch-Nyhan disease ; Purines ; ZMP
Publicat a:	Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Núm. 22 (June 2020) , p. 12071-12079, ISSN 1091-6490

DOI: 10.1073/pnas.2003475117
PMID: 32430324

9 p, 845.3 KB

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