A fly GWAS for purine metabolites identifies human FAM214 homolog medusa, which acts in a conserved manner to enhance hyperuricemia-driven pathologies by modulating purine metabolism and the inflammatory response
Autor: | Tyler A. U. Hilsabeck, Ru Liu-Bryan, Tracy Guo, Kenneth A. Wilson, Neelanjan Bose, Daniel Raftery, Jennifer N. Beck, Sven Lang, Kelly Jin, Christopher S. Nelson, Tal Oron, Marshall Stoller, Daniel Promislow, Rachel B. Brem, Robert Terkeltaub, Pankaj Kapahi |
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Rok vydání: | 2022 |
Předmět: |
Inflammation
Aging Gout Lifespan Inflammatory and immune system nutritional and metabolic diseases Hyperuricemia Uric Acid Mice Drosophila melanogaster Purines Genetics Animals Humans Drosophila Proteins GWAS 2.1 Biological and endogenous factors Original Article Drosophila Geriatrics and Gerontology Aetiology Genome-Wide Association Study Biotechnology |
Zdroj: | GeroScience, vol 44, iss 4 GeroScience |
Popis: | Elevated serum urate (hyperuricemia) promotes crystalline monosodium urate tissue deposits and gout, with associated inflammation and increased mortality. To identify modifiers of uric acid pathologies, we performed a fly Genome-Wide Association Study (GWAS) on purine metabolites using the Drosophila Genetic Reference Panel strains. We tested the candidate genes using the Drosophila melanogaster model of hyperuricemia and uric acid crystallization (“concretion formation”) in the kidney-like Malpighian tubule. Medusa (mda) activity increased urate levels and inflammatory response programming. Conversely, whole-body mda knockdown decreased purine synthesis precursor phosphoribosyl pyrophosphate, uric acid, and guanosine levels; limited formation of aggregated uric acid concretions; and was sufficient to rescue lifespan reduction in the fly hyperuricemia and gout model. Levels of mda homolog FAM214A were elevated in inflammatory M1- and reduced in anti-inflammatory M2-differentiated mouse bone marrow macrophages, and influenced intracellular uric acid levels in human HepG2 transformed hepatocytes. In conclusion, mda/FAM214A acts in a conserved manner to regulate purine metabolism, promotes disease driven by hyperuricemia and associated tissue inflammation, and provides a potential novel target for uric acid–driven pathologies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00557-9. |
Databáze: | OpenAIRE |
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