Abstract
Lysosomal storage disorders (LSDs) are predominantly very rare recessive autosomal neurodegenerative diseases.Sphingolipidoses, a sub-group of LSDs, result from defects in lysosomal enzymes involved in sphingolipid catabolism, and feature disrupted storage systems which trigger complex pathogenic cascades with other organelles collaterally affected. This process leads to cell dysfunction and death, particularly in the central nervous system. One valuable approach to gaining insights into the global impact of lysosomal dysfunction is through metabolomics, which represents a discovery tool for investigating disease-induced modifications in the patterns of large numbers of simultaneously-analysed metabolites, which also features the identification of biomarkers Here, the scope and applications of metabolomics strategies to the investigation of sphingolipidoses is explored in order to facilitate our understanding of the biomolecular basis of these conditions. This review therefore surveys the benefits of applying ’state-of-the-art’ metabolomics strategies, both univariate and multivariate, to sphingolipidoses, particularly Niemann-Pick type C disease. Relevant limitations of these techniques are also discussed, along with the latest advances and developments. We conclude that metabolomics strategies are highly valuable, distinctive bioanalytical techniques for probing LSDs, most especially for the detection and validation of potential biomarkers. They also show much promise for monitoring disease progression and the evaluation of therapeutic strategies and targets.
Highlights
In the functional lysosome, lipids and other macromolecules, such as carbohydrates, peptides, and nucleic acids, are degraded through the action of acid hydrolases
High-resolution 1H nuclear magnetic resonance (NMR) analysis has been successful in identifying potential urinary biomarkers for Niemann-Pick disease type C1 (NPC1) disease diagnosis, and these include branched-chain amino acids (BCAAs), selected bile acids and 3-aminoisobutyrate [22], the latter arising from either BCAA catabolism or thymine degradation. These analyses further indicated that the brain and liver were the prominent sites affected, an observation which is consistent with its disease manifestations, including seizures and hepatomegaly
These included elevated levels of ceramide, GM1, GM3, sphingolipid species, and lactosylceramide in NPC1 tissues, which markedly reduced upon treatment with HPβCD, an effect greater than that observed with miglustat treatment [9]
Summary
Lipids and other macromolecules, such as carbohydrates, peptides, and nucleic acids, are degraded through the action of acid hydrolases. Biofluid or tissue biopsy ‘patterns’ or ‘signatures’ of metabolites which are representative of a particular LSD process (and potentially encompassing a range of such biomarkers, each with highly significantly up- or downregulated concentrations) will, at least in principle, provide a much higher level of confidence regarding the diagnosis, prognosis and response to treatment of such disorders than that realisable from a single biomarker; second, the metabolic patterns detected and determined, together with their correlations to particular components or factors [linear and/or sometimes quadratic combinations of predictor biomarker variables] provide extensive and valuable information regarding the nature of the metabolic stress response(s) or disturbance(s), e.g., pathogenic imbalances in amino acid, amino-sugar, fatty acid and nucleotide metabolism, TCA cycle intermediates, etc., and the class of organ and tissue damage (e.g., neurodegeneration), together with the sub-cellular localizations involved; third, the identification of ‘suppressor’ variables, i.e., those which do not directly provide disease classification information but exert a significant and sometimes substantial influence on reliable biomarker level variables themselves, are detectable using correlated component regression (CCR) approaches [8]. 56 NPC1 56 Controls 109 NPC1 88 Controls 45 Heterozygous carriers 5 NPC1 7 Controls
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