Decrease in Myelin-Associated Lipids Precedes Neuronal Loss and Glial Activation in the CNS of the Sandhoff Mouse as Determined by Metabolomics.

Emmanuelle Lecommandeur,Julian L Griffin,Andrew W Nicholls,Susannah Boddie,Maria Begoña Cachón-González,Timothy M Cox,Ben D Mcnally

doi:10.3390/metabo11010018

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 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.

Highlights

Sandhoff disease (SD) is a GM2 gangliosidosis caused by mutations in the gene encoding the β subunit of βhexosaminidase (HEXB), leading to a deficiency in the lysosomal enzymes β-hexosaminidaseA (HEX A) and B (HEX B) [1]
GM2 affects all the central nervous system (CNS) but the initial microscopic neuropathology is in the cerebrum which is neurone rich in the cortex, and clinically associated with the rapid dementia
SDatataametabolic metaboliclevel, level,with withnumerous numerousabnormalities abnormalities in diverse metabolites affected in the mouse model of in diverse metabolites affected in the mouse model of SD (Figure 8)

Summary

Introduction

Sandhoff disease (SD) is a GM2 gangliosidosis (in the abbreviation GM2, G refers to ganglioside, the M is for monosialic, and 2 refers to the fact that it was the second monosialic ganglioside discovered) caused by mutations in the gene encoding the β subunit of βhexosaminidase (HEXB), leading to a deficiency in the lysosomal enzymes β-hexosaminidaseA (HEX A) and B (HEX B) [1]. Sandhoff disease (SD) is a GM2 gangliosidosis (in the abbreviation GM2, G refers to ganglioside, the M is for monosialic, and 2 refers to the fact that it was the second monosialic ganglioside discovered) caused by mutations in the gene encoding the β subunit of βhexosaminidase (HEXB), leading to a deficiency in the lysosomal enzymes β-hexosaminidase. HEX A and HEX B cleave N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) residues from a variety of substrates, including ganglioside GM2, abundant in nervous tissue. Over 50 different disease-causing mutations in HEXB have been reported [2], giving rise to a wide spectrum of disease onset and symptoms. Accumulation of gangliosides GM2 and GA2 (asialylated GM2) is detected throughout the central nervous system (CNS). The unacylated ganglioside, lyso-GM2 has been reported to be increased in the brain and plasma of SD patients and in the mouse model [5]

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