Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease
- Author(s)
- Green, CR; Bonelli, R; Ansell, BRE; Tzaridis, S; Handzlik, MK; McGregor, GH; Hart, B; Trombley, J; Reilly, MM; Bernstein, PS; Egan, C; Fruttiger, M; Wallace, M; Bahlo, M; Friedlander, M; Metallo, CM; Gantner, ML;
- Journal Title
- Molecular Metabolism
- Abstract
- OBJECTIVES: The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both. METHODS: We performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants. RESULTS: MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model of retinopathy indicates dietary serine and restriction can drive this depletion in complex sphingolipids. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins. CONCLUSIONS: These results highlight metabolic distinctions between these two diseases, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches.
- Publisher
- Elsevier
- Keywords
- Amino acids; Hsan1; Macular telangiectasia; Peripheral neuropathy; Retinopathy; Sphingolipids
- Research Division(s)
- Population Health And Immunity
- PubMed ID
- 36997154
- Publisher's Version
- https://doi.org/10.1016/j.molmet.2023.101716
- Open Access at Publisher's Site
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Creation Date: 2023-04-18 01:58:45
Last Modified: 2023-04-18 02:49:25