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

Green, Courtney R; Bonelli, Roberto; Ansell, Brendan RE; Tzaridis, Simone; Handzlik, Michal K; McGregor, Grace H; Hart, Barbara; ... Gantner, Marin L; + view all (2023) Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease. Molecular Metabolism , 72 , Article 101716. 10.1016/j.molmet.2023.101716. Green open access

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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 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. CONCLUSIONS: 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.

Type: Article
Title: Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease
Location: Germany
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.molmet.2023.101716
Publisher version: https://doi.org/10.1016/j.molmet.2023.101716
Language: English
Additional information: © 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Keywords: Amino acids, HSAN1, Macular telangiectasia, Peripheral neuropathy, Retinopathy, Sphingolipids
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10168202
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