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Metabolomics profiling reveals profound metabolic impairments in mice and patients with Sandhoff disease.
Ou, Li; Przybilla, Michael J; Whitley, Chester B.
Afiliação
  • Ou L; Gene Therapy Center, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: ouxxx045@umn.edu.
  • Przybilla MJ; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, United States.
  • Whitley CB; Gene Therapy Center, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, United States; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, United States.
Mol Genet Metab ; 126(2): 151-156, 2019 02.
Article em En | MEDLINE | ID: mdl-30236619
Sandhoff disease (SD) results from mutations in the HEXB gene, subsequent deficiency of N-acetyl-ß-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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Sandhoff / Metaboloma Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Mol Genet Metab Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA / METABOLISMO Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Sandhoff / Metaboloma Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Mol Genet Metab Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA / METABOLISMO Ano de publicação: 2019 Tipo de documento: Article