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

Animals Mice Amino Acids Sphingomyelins Sphingolipids / metabolism Retinal Diseases Serine / metabolism Alanine Glycine Hereditary Sensory and Autonomic Neuropathies
Amino acids HSAN1 Macular telangiectasia Peripheral neuropathy Retinopathy Sphingolipids

Journal

Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730

Informations de publication

Date de publication:
06 2023
Historique:
received: 08 02 2023
revised: 15 03 2023
accepted: 23 03 2023
medline: 8 5 2023
pubmed: 31 3 2023
entrez: 30 3 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.molmet.2023.101716 PMID: 36997154 PMC: PMC10114224
pubmed: 36997154
pii: S2212-8778(23)00050-9
doi: 10.1016/j.molmet.2023.101716
pmc: PMC10114224
pii:
doi:

Substances chimiques

Amino Acids 0
Sphingomyelins 0
Sphingolipids 0
Serine 452VLY9402
Alanine OF5P57N2ZX
Glycine TE7660XO1C

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

101716

Subventions

Organisme : NCI NIH HHS
ID : R01 CA234245
Pays : United States

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Auteurs

Courtney R Green (CR)

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 (R)

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 (BRE)

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 (S)

Lowy Medical Research Institute, La Jolla, CA, USA.

Michal K Handzlik (MK)

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 (GH)

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 (B)

Moran Eye Center, University of Utah, Salt Lake City, UT, USA.

Jennifer Trombley (J)

Lowy Medical Research Institute, La Jolla, CA, USA.

Mary M Reilly (MM)

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.

Paul S Bernstein (PS)

Moran Eye Center, University of Utah, Salt Lake City, UT, USA.

Catherine Egan (C)

Medical Retina Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK; University College London Institute of Ophthalmology, London, UK.

Marcus Fruttiger (M)

University College London Institute of Ophthalmology, London, UK.

Martina Wallace (M)

University College Dublin, Dublin, Ireland.

Melanie Bahlo (M)

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 (M)

Lowy Medical Research Institute, La Jolla, CA, USA.

Christian M Metallo (CM)

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. Electronic address: metallo@salk.edu.

Marin L Gantner (ML)

Lowy Medical Research Institute, La Jolla, CA, USA. Electronic address: mgantner@lmri.net.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Lipides › Lipides membranaires › Sphingolipides › Glycosphingolipides › Glycosphingolipides neutres › Sphingomyéline › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Lipides › Lipides membranaires › Sphingolipides › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Maladies de l'oeil › Rétinopathies › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés neutres › Sérine › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Alanine › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Glycine › Divergent amino acid and sphingolipid...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies neurodégénératives héréditaires › Neuropathies héréditaires sensitives et autonomes › Divergent amino acid and sphingolipid...