GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease.

Autor:	Senkevich K; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal H3A 2B4, Canada., Zorca CE; Department of Neurology and Neurosurgery, McGill University, Montréal H3A 2B4, Canada.; Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal H3A 2B4, Canada., Dworkind A; Department of Physiology, McGill University, Montréal H3A 1A1, Canada., Rudakou U; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal H3A 2B4, Canada.; Department of Human Genetics, McGill University, Montréal H3A 1A1, Canada., Somerville E; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.; Department of Human Genetics, McGill University, Montréal H3A 1A1, Canada., Yu E; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.; Department of Human Genetics, McGill University, Montréal H3A 1A1, Canada., Ermolaev A; Center of Molecular Biotechnology, Russian State Agrarian University-Moscow Timiryazev Agricultural Academy, Moscow 127550, Russia.; ȃResearch Department, Bioinformatics Institute, Saint-Petersburg 194100, Russia., Nikanorova D; ȃResearch Department, Bioinformatics Institute, Saint-Petersburg 194100, Russia., Ahmad J; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal H3A 2B4, Canada., Ruskey JA; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal H3A 2B4, Canada., Asayesh F; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.; Department of Human Genetics, McGill University, Montréal H3A 1A1, Canada., Spiegelman D; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada., Fahn S; Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032-3784, USA., Waters C; Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032-3784, USA., Monchi O; Department of Neurology and Neurosurgery, McGill University, Montréal H3A 2B4, Canada.; Department of Clinical Neurosciences and Department of Radiology, University of Calgary, Calgary T2N 1N4, Canada.; Hotchkiss Brain Institute, Cumming School of Medicine, Calgary T2N 4N1, Canada., Dauvilliers Y; ȃNational Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, 34090 Montpellier, France., Dupré N; Neuroscience Axis, CHU de Québec-Université Laval, Quebec City G1V 4G2, Canada.; Department of Medicine, Faculty of Medicine, Université Laval, Québec G1V 0A6, Canada., Greenbaum L; ȃThe Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer 52621, Israel.; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel., Hassin-Baer S; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.; Department of Neurology, The Movement Disorders Institute, Sheba Medical Center, Tel Hashomer 52621, Israel., Grenn FP; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA., Chiang MSR; Rare and Neurologic Diseases Therapeutic Area, Sanofi, Framingham, MA 01701, USA., Sardi SP; Rare and Neurologic Diseases Therapeutic Area, Sanofi, Framingham, MA 01701, USA., Vanderperre B; Département des sciences biologiques, Université du Québec à Montréal, Montréal H2X 1Y4, Canada., Blauwendraat C; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA., Trempe JF; Department of Pharmacology and Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, Montreal H3A 1A3, Canada., Fon EA; Department of Neurology and Neurosurgery, McGill University, Montréal H3A 2B4, Canada.; Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal H3A 2B4, Canada., Durcan TM; Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal H3A 2B4, Canada., Alcalay RN; Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032-3784, USA.; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA., Gan-Or Z; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal H3A 2B4, Canada.; Department of Human Genetics, McGill University, Montréal H3A 1A1, Canada.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2023 May 02; Vol. 146 (5), pp. 1859-1872.
DOI:	10.1093/brain/awac413
Abstrakt:	The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10-95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity. Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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