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

Courtney R. Green; Roberto Bonelli; Brendan R.E. Ansell; Simone Tzaridis; Michal K. Handzlik; Grace H. McGregor; Barbara Hart; Jennifer Trombley; Mary M. Reilly; Paul S. Bernstein; Catherine Egan; Marcus Fruttiger; Martina Wallace; Melanie Bahlo; Martin Friedlander; Christian M. Metallo; Marin L. Gantner

Molecular Metabolism (Jun 2023)

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

Courtney R. Green,
Roberto Bonelli,
Brendan R.E. Ansell,
Simone Tzaridis,
Michal K. Handzlik,
Grace H. McGregor,
Barbara Hart,
Jennifer Trombley,
Mary M. Reilly,
Paul S. Bernstein,
Catherine Egan,
Marcus Fruttiger,
Martina Wallace,
Melanie Bahlo,
Martin Friedlander,
Christian M. Metallo,
Marin L. Gantner

Affiliations

Courtney R. Green: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, CA, USA
Roberto Bonelli: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
Brendan R.E. Ansell: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
Simone Tzaridis: Lowy Medical Research Institute, La Jolla, CA, USA
Michal K. Handzlik: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, CA, USA
Grace H. McGregor: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, CA, USA
Barbara Hart: Moran Eye Center, University of Utah, Salt Lake City, UT, USA
Jennifer Trombley: Lowy Medical Research Institute, La Jolla, CA, USA
Mary M. Reilly: Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
Paul S. Bernstein: Moran Eye Center, University of Utah, Salt Lake City, UT, USA
Catherine Egan: Medical Retina Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK; University College London Institute of Ophthalmology, London, UK
Marcus Fruttiger: University College London Institute of Ophthalmology, London, UK
Martina Wallace: University College Dublin, Dublin, Ireland
Melanie Bahlo: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
Martin Friedlander: Lowy Medical Research Institute, La Jolla, CA, USA
Christian M. Metallo: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, CA, USA; Corresponding author. Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
Marin L. Gantner: Lowy Medical Research Institute, La Jolla, CA, USA; Corresponding author. Lowy Medical Research Institute, La Jolla, CA, USA

Journal volume & issue: Vol. 72
p. 101716

Abstract

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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.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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