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[Preprint]. 2024 Sep 16:2024.09.13.24313644.
doi: 10.1101/2024.09.13.24313644.

Plasma glucosylceramide levels are regulated by ATP10D and are not involved in Parkinson's disease pathogenesis

Emma N Somerville  1   2 , Alva James  3 , Christian Beetz  3 , Robert Schwieger  3 , Gal Barrel  3 , Krishna K Kandaswamy  4   3 , Marius I Iurascu  4   3 , Peter Bauer  3 , Michael Ta  4   5 , Hirotaka Iwaki  4   5 , Konstantin Senkevich  1   6 , Eric Yu  1   2 , Roy N Alcalay  7   8   9 , Ziv Gan-Or  1   2   6
Affiliations

Plasma glucosylceramide levels are regulated by ATP10D and are not involved in Parkinson's disease pathogenesis

Emma N Somerville et al. medRxiv. .

Update in

Abstract

GBA1 variants and decreased glucocerebrosidase (GCase) activity are implicated in Parkinson's disease (PD). We investigated the hypothesis that increased levels of glucosylceramide (GlcCer), one of GCase main substrates, are involved in PD pathogenesis. Using multiple genetic methods, we show that 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.

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Conflict of interest statement

Potential Conflicts of Interest A.J., C.B., R.S., G.B., K.K.K., M.I.I., and P.B are current or previous employees of CENTOGENE GmbH, which is investigating the role of GlcCer in PD for investigational therapy development. H.I. and M.T.’s participation in this project was part of a competitive contract awarded to Data Tecnica LLC by the National Institutes of Health to support open science research. Z.G.O received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua bio, Congruence Therapeutics, Takeda, Jazz Guidepoint, Lighthouse and Deerfield for development of GBA1-related therapeutics.

Figures

Figure 1.
Figure 1.
A) Manhattan plot of log adjusted p-values at each genomic position for GWAS of total GlcCer levels in the PPMI cohort adjusted for age, sex, disease status, and 5 PCs, B) Locuszoom Manhattan plot of the ATP10D gene region in the PD GWAS, C) Area under the curve 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.
See this image and copyright information in PMC

References

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