10.3390/metabo11010018 Decrease in Myelin-Associated Lipids Precedes Neuronal Loss and Glial Activation in the CNS of the Sandhoff Mouse as Determined by Metabolomics Lecommandeur Emmanuelle Dr. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK emmanuelle.lecommandeur@gmail.com Cachón-González Maria Begoña Dr. Department of Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK mcb23@medschl.cam.ac.uk Boddie Susannah Dr. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK boddiesusannah@gmail.com McNally Ben D. Dr. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK mcnallyb14@gmail.com Nicholls Andrew W. Dr. GlaxoSmithKline, Stevenage SG1 2NY, UK andrew.w.nicholls@gsk.com Cox Timothy M. Dr. Department of Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK tmc12@medschl.cam.ac.uk Griffin Julian L. Dr. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK Hammersmith Campus, UK Dementia Research Institute at Imperial College, Burlington Danes Building, Imperial College London, Du Cane Road, London W12 0NN, UK Section of Biomolecular Medicine, Department of Metabolism, Division of Systems Medicine, Digestion and Reproduction, The Sir Alexander Fleming Building, Exhibition Road, South Kensington, Imperial College London, London SW7 2AZ, UK jlg30@ic.ac.uk 30 12 2020 11 1 21 12 2020 e18 Sandhoff disease (SD) is a lysosomal disease caused by mutations in the gene coding for the β subunit of β-hexosaminidase, leading to deficiency in the enzymes β-hexosaminidase (HEX) A and B. SD is characterised by an accumulation of gangliosides and related glycolipids, mainly in the central nervous system, and progressive neurodegeneration. The underlying cellular mechanisms leading to neurodegeneration and the contribution of inflammation in SD remain undefined. The aim of the present study was to measure global changes in metabolism over time that might reveal novel molecular pathways of disease. We used liquid chromatography-mass spectrometry and ¹H Nuclear Magnetic Resonance spectroscopy to profile intact lipids and aqueous metabolites, respectively. We examined spinal cord and cerebrum from healthy and Hexb^−/− mice, a mouse model of SD, at ages one, two, three and four months. We report decreased concentrations in lipids typical of the myelin sheath, galactosylceramides and plasmalogen-phosphatidylethanolamines, suggesting that reduced synthesis of myelin lipids is an early event in the development of disease pathology. Reduction in neuronal density is progressive, as demonstrated by decreased concentrations of N-acetylaspartate and amino acid neurotransmitters. Finally, microglial activation, indicated by increased amounts of myo-inositol correlates closely with the late symptomatic phases of the disease. Medical Research Council UD99999906 UK Dementia Research Institute NA © 1996-2021 MDPI (Basel, Switzerland) 2020 This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited lipidomics metabolomics lysosomal disorders β-hexosaminidase galactosylceramides bis(monoacylglycero)phosphates plasmalogens Metabolites Metabolites 2218-1989 MDPI