Glucosylsphingosine affects mitochondrial function in a neuronal cell model.

Gaucher disease arises from mutations in glucocerebrosidase resulting in accumulation of glucosylceramide, which is deacylated to glucosylsphingosine. Mutations in glucocerebrosidase are the greatest known genetic risk factor for Parkinson's disease. Glucosylsphingosine is a biomarker for Gaucher disease and studies demonstrate its relevance to disease pathology, yet the mechanisms of its toxicity remain little understood. Using proteomics, we show that incubation of SH-Sy5y cells with glucosylsphingosine at physiological plasma concentrations observed in moderate/ severe Gaucher disease negatively effects the TCA cycle, mitochondrial function, glycolysis and protein ubiquitination. Functional analyses confirmed that glucosylsphingosine reduces ATP production, elicits oxidative stress and an increase of glycolysis. Analyses of ubiquitinated proteins and lipid-binding studies demonstrated that glucosylsphingosine has binding affinity for tubulin alpha and induced a specific increase of ubiquitination of α and β tubulins. In conclusion, supranormal levels of glucosylsphingosine affect cellular energy metabolism which may contribute to the pathology in Gaucher disease.