Metabolomics profiling reveals profound metabolic impairments in mice and patients with Sandhoff disease

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Abstract

Sandhoff disease (SD) results from mutations in the HEXB gene, subsequent deficiency of N-acetyl-β-hexosaminidase (Hex) and accumulation of GM2 gangliosides. SD leads to progressive neurodegeneration and early death. However, there is a lack of established SD biomarkers, while the pathogenesis etiology remains to be elucidated. To identify potential biomarkers and unveil the pathogenic mechanisms, metabolomics analysis with reverse phase liquid chromatography (RPLC) was conducted. A total of 177, 112 and 119 metabolites were found to be significantly dysregulated in mouse liver, mouse brain and human hippocampus samples, respectively (p <.05, ID score > 0.5). Principal component analysis (PCA) analysis of the metabolites showed clear separation of metabolomics profiles between normal and diseased individuals. Among these metabolites, dipeptides, amino acids and derivatives were elevated, indicating a robust protein catabolism. Through pathway enrichment analysis, we also found alterations in metabolites associated with neurotransmission, lipid metabolism, oxidative stress and inflammation. In addition, N-acetylgalactosamine 4-sulphate, key component of glycosaminoglycans (GAG) was significantly elevated, which was also confirmed by biochemical assays. Collectively, these results indicated major shifts of energy utilization and profound metabolic impairments, contributing to the pathogenesis mechanisms of SD. Global metabolomics profiling may provide an innovative tool for better understanding the disease mechanisms, and identifying potential diagnostic biomarkers for SD.

Original languageEnglish (US)
Pages (from-to)151-156
Number of pages6
JournalMolecular Genetics and Metabolism
Volume126
Issue number2
DOIs
StatePublished - Feb 2019

Bibliographical note

Funding Information:
The authors thank the Proteomics & Mass Spectrometry Facility at the Danforth Plant Science Center (St. Louis, MO) for metabolic profiling analyses. All authors declare that they have no conflicts of interest related to this work. This work is supported by NIH grant P01HD032652 . Dr. Li Ou is a fellow of the Lysosomal Disease Network ( U54NS065768 ). The Lysosomal Disease Network is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Funding Information:
The authors thank the Proteomics & Mass Spectrometry Facility at the Danforth Plant Science Center (St. Louis, MO) for metabolic profiling analyses. All authors declare that they have no conflicts of interest related to this work. This work is supported by NIH grant P01HD032652. Dr. Li Ou is a fellow of the Lysosomal Disease Network (U54NS065768). The Lysosomal Disease Network is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Publisher Copyright:
© 2018 Elsevier Inc.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • Biomarker
  • GM2 gangliosidosis
  • Metabolomics
  • Sandhoff disease

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