Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease

• Published in: Molecular metabolism (Germany) 2023-06, Vol.72, p.101716-101716, Article 101716
• Main Authors: Green, Courtney R., Bonelli, Roberto, Ansell, Brendan R.E., Tzaridis, Simone, Handzlik, Michal K., McGregor, Grace H., Hart, Barbara, Trombley, Jennifer, Reilly, Mary M., Bernstein, Paul S., Egan, Catherine, Fruttiger, Marcus, Wallace, Martina, Bahlo, Melanie, Friedlander, Martin, Metallo, Christian M., Gantner, Marin L.
• Format: Article
• Language: English
• Subjects: Alanine; Amino Acids; Animals; Glycine; Hereditary Sensory and Autonomic Neuropathies; HSAN1; Macular telangiectasia; Mice; Original; Peripheral neuropathy; Retinal Diseases; Retinopathy; Serine - metabolism; Sphingolipids; Sphingolipids - metabolism; Sphingomyelins
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2023.101716

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. 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. 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 glycine 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. These results highlight metabolic distinctions between MacTel and HSAN1, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches for these two neurodegenerative diseases. •Comprehensive quantification of sphingolipids & amino acids in human sera, including two rare neuropathies.•The retinopathy, MacTel, is a metabolic disease of impaired amino acid metabolism, mirroring aspects of diabetes.•Serine and glycine impact sphingolipid metabolism via multiple mechanisms.•Reduced membrane sphingomyelin and glycosphingolipids in circulation are associated with MacTel.•Opposing amino acid and sphingolipid changes in MacTel and HSAN1 suggest distinct therapeutic approaches.