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

Autor:	Somerville EN; The Neuro (Montréal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.; Department of Human Genetics, McGill University, Montréal, QC, Canada., James A; CENTOGENE GmbH, Rostock, Germany., Beetz C; CENTOGENE GmbH, Rostock, Germany., Schwieger R; CENTOGENE GmbH, Rostock, Germany., Barrel G; CENTOGENE GmbH, Rostock, Germany., Kandaswamy KK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; CENTOGENE GmbH, Rostock, Germany., Iurascu MI; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; CENTOGENE GmbH, Rostock, Germany., Bauer P; CENTOGENE GmbH, Rostock, Germany., Ta M; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Data Tecnica International, Washington, DC, USA., Iwaki H; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Data Tecnica International, Washington, DC, USA., Senkevich K; The Neuro (Montréal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada., Yu E; The Neuro (Montréal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.; Department of Human Genetics, McGill University, Montréal, QC, Canada., Alcalay RN; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Gan-Or Z; The Neuro (Montréal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.; Department of Human Genetics, McGill University, Montréal, QC, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Sep 16. Date of Electronic Publication: 2024 Sep 16.
DOI:	10.1101/2024.09.13.24313644
Abstrakt:	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. Competing Interests: 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.
Databáze:	MEDLINE
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