Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease

• Authors: Jose M. Lopez, Universitat Autònoma de Barcelona; Esther L. Outtrim, Emory University; Rong Fu, Emory University; Diane J. Sutcliffe, Emory University; Rosa J. Torres, Instituto de Salud Carlos III; Hyder Jinnah, Emory University
• Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: Volume 117, Number 22
• Publisher: NATL ACAD SCIENCES | 2020-06-02, Pages 12071-12079
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.2003475117
• Subjects: Biology, Physiology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; purines; folic acid; Lesch-Nyhan disease; ZMP; AICAr; ACTIVATED PROTEIN-KINASE; 5-AMINO-4-IMIDAZOLECARBOXAMIDE RIBOSIDE; ENZYMATIC-SYNTHESIS; URINARY-EXCRETION; METABOLISM; BIOSYNTHESIS; ACCUMULATION; MODEL; AMINOIMIDAZOLECARBOXAMIDE; DEFICIENT

Abstract

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.