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

作者：Konstantin Senkevich, Cornelia E. Zorca, Aliza Dworkind, Uladzislau Rudakou, Emma N. Somerville, Eric Yu, Aleksey Ermolaev, Daria Nikanorova, Jamil Ahmad, Jennifer A. Ruskey, Farnaz Asayesh, Dan Spiegelman, Stanley Fahn, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Nicolas Dupré, Lior Greenbaum, Sharon Hassin‐Baer, Francis P. Grenn, Ming Sum Ruby Chiang, S. Pablo Sardi, Benoît Vanderperre, Cornelis Blauwendraat, Jean‐François Trempe, Edward A. Fon, Thomas M. Durcan, Roy N. Alcalay, Ziv Gan‐Or · 发表于：Brain · 年份：2022 · DOI：10.1093/brain/awac413 · 被引用次数：39 · 研究领域：Lysosomal Storage Disorders Research、Parkinson's Disease Mechanisms and Treatments、Trypanosoma species research and implications

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 analy...