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Cited by 40Lysosomal Storage Disorders ResearchParkinson's Disease Mechanisms and TreatmentsMetabolism and Genetic Disorders

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

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Senkevich, Konstantin, Zorca, Cornelia E, Dworkind, Aliza, Rudakou, Uladzislau, Somerville, Emma, Yu, Eric, Ermolaev, Alexey, Nikanorova, Daria +21 more·2023·Brain
DOI 10.1093/brain/awac413PMC PMC10151180
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Abstract

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.

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  • Almost 50% of proteins in the mammalian proteome feature a KFERQ-like motif, including TDP-43, alpha-synuclein, APP, and tau.

    “Almost 50% of the proteins in the mammalian proteome feature a KFERQ-like motif, including all the major aggregating proteins of neurodegenerative diseases (i.e., TDP-43, alpha-synuclein, APP, and tau).99,143–145”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [143]

    The Results section discusses GALC structure, and the Materials and methods section describes an alpha-synuclein assay. Neither the supplied passages nor searches for KFERQ-like motifs, the 50% estimate, TDP-43, APP, and tau found a passage addressing the claim. (LLM, conf=0.76)

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Authors
Senkevich, K., Zorca, C. E., Dworkind, A., Rudakou, U., Somerville, E., Yu, E., Ermolaev, A., Nikanorova, D., Ahmad, J., Ruskey, J. A., Asayesh, F., Spiegelman, D., Fahn, S., Waters, C., Monchi, O., Dauvilliers, Y., Dupré, N., Greenbaum, L., Hassin-Baer, S., Grenn, F. P., Chiang, M. S. R., Sardi, S. P., Vanderperre, B., Blauwendraat, C., Trempe, J.-F., Fon, E. A., Durcan, T. M., Alcalay, R. N., & Gan-Or, Z.
Affiliations
  • Montreal Neurological Institute and Hospital (CA)
  • McGill University (CA)
  • Center of Molecular Biotechnology, Russian State Agrarian University-Moscow Timiryazev Agricultural Academy , Moscow 127550 , Russia
  • Bioinformatics Institute (RU)
  • Columbia University Irving Medical Center (US)
  • University of Calgary (CA)
  • Inserm (FR)
  • Université Laval (CA)
  • Tel Aviv University (IL)
  • Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978 , Israel
  • National Institutes of Health (US)
  • Sanofi (United States) (US)
  • Université du Québec à Montréal (CA)
  • The Neuro (Montreal Neurological Institute-Hospital), McGill University , Montreal H3A 2B4 , Canada
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2022-11-11
Volume
146
Issue
5
Pages
1859-1872
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awac413
PMC
PMC10151180
OpenAlex
W4308834678
Cited by
40
References
7
Citations by year
2026: 9 · 2025: 17 · 2024: 7 · 2023: 4 · 2022: 3
FWCI
1.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Michael J. Fox Foundation
  • Canadian Consortium on Neurodegeneration in Aging
  • Canada First Research Excellence Fund
  • Parkinson’s Foundation
  • National Institutes of Health (K02NS080915, UL1 TR000040)
  • Brookdale Foundation
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
Parkinson's disease, GALC, lysosomal enzymes, glycosphingolipid metabolism, alpha-synuclein accumulation, glucocerebrosidase, causal relationship, rare variants, Parkinson's Progression Markers Initiative
MeSH terms
Galactosylceramidase, Glucosylceramidase, Humans, Hydrolases, Mutation, Parkinson Disease, alpha-Synuclein, Genome-Wide Association Study

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