Decrease in Myelin-Associated Lipids Precedes Neuronal Loss and Glial Activation in the CNS of the Sandhoff Mouse as Determined by Metabolomics
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Authors
Griffin, julian L
Lecommandeur, Emanuelle
Boddie, Susannah
McNally, Ben
Nicholls, Andrew
Journal Title
Metabolites
ISSN
2218-1989
Publisher
MDPI AG
Type
Article
This Version
AM
Metadata
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Cox, T., Griffin, j. L., Lecommandeur, E., Cachon-Gonzalez, B., Boddie, S., McNally, B., & Nicholls, A. Decrease in Myelin-Associated Lipids Precedes Neuronal Loss and Glial Activation in the CNS of the Sandhoff Mouse as Determined by Metabolomics. Metabolites https://doi.org/10.17863/CAM.62907
Abstract
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 mecha-nisms leading to neurodegeneration and the contribution of inflammation in SD remain unde-fined. 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 spec-trometry 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 pro-gressive, 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.
Sponsorship
National Institute for Health Research ()
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG50826 METABOLISM)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Embargo Lift Date
2024-01-06
Identifiers
This record's DOI: https://doi.org/10.17863/CAM.62907
This record's URL: https://www.repository.cam.ac.uk/handle/1810/315798
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