Plasma Glucosylceramide Levels Are Regulated by ATP10D and Are Not Involved in Parkinson's Disease Pathogenesis

Abstract

GBA1 variants and decreased glucocerebrosidase activity are implicated in Parkinson's disease (PD). We investigated the hypothesis that increased levels of glucosylceramide (GlcCer), a main substrate of glucocerebrosidase, are involved in PD pathogenesis. Using multiple genetic methods, we show that ATPase phospholipid transporting 10D (ATP10D), not GBA1, is the main regulator of plasma GlcCer levels, yet it is not involved in PD pathogenesis. Plasma GlcCer levels were associated with PD, but not in a causative manner, and are not predictive of disease status. These results argue against targeting GlcCer in GBA1-PD, and underscore the need to explore alternative mechanisms and biomarkers for PD. ANN NEUROL 2025;97:873-878.

FIGURE 1

(A) Manhattan plot of log adjusted p values at each genomic position for GWAS of total glucosylceramide (GlcCer) levels in the PPMI cohort adjusted for age, sex, disease status, and 5 PCs. (B) Locuszoom Manhattan plot of the ATPase phospholipid transporting 10D (ATP10D) gene region in the Parkinson's disease (PD) genome‐wide association study (GWAS). (C) Area under the curve (AUC) analysis for logistic regressions of total GlcCer with PD status, with and without adjustment for the lead ATP10D GWAS hit. (D) Colocalization plot comparing ATP10D locus p values in the total GlcCer levels GWAS and the PD GWAS. LD = linkage disequilibrium; PC= principal component.