Plasma Glucosylsphingosine in GBA1 E365K, N409S, and L483P Heterozygous Mutation Carriers

Background: GBA1 encodes the lysosomal enzyme glucocerebrosidase, with key substrates that include glucosylceramide and glucosylsphingosine. The E365K variant is the most common variant in GBA1 that is associated with Parkinson's disease (PD) but is not associated with Gaucher disease. Plasma glucosylsphingosine levels have previously been shown to be higher in GBA1 N409S heterozygous carriers, but its levels in E365K carriers are unknown. Objective: The aim was to measure plasma glucosylsphingosine levels in GBA1 N409S, E365K, and L483P heterozygous mutation carriers with and without PD. Methods: Glucosylsphingosine was quantified in plasma from 112 participants using liquid chromatography–tandem mass spectrometry targeted quantification. Results: Plasma glucosylsphingosine concentration was significantly higher in N409S (0.59 ng/mL, p = 0.004), E365K (0.59 ng/mL, p = 0.01), and L483P (0.63 ng/mL, p = 0.003) heterozygotes compared to noncarriers (0.45 ng/mL), independent of disease status. Conclusions: Elevated plasma glucosylsphingosine confirms reduced glucocerebrosidase function in E365K carriers.