Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis

Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis

Abstract Bi-allelic pathogenic GBA1 variants cause Gaucher disease (GD), whereas certain heterozygous missense variants increase the risk of Parkinson’s disease (PD), although the underlying mechanisms are unclear. Here, we classified GBA1 missense variants using predictive and structural scores, an...

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Main Authors: Aymeric Lanore, Christelle Tesson, Aymeric Basset, François-Xavier Lejeune, Guillaume Cogan, Graziella Mangone, Sara Sambin, Nathalie Bertille, Mathieu Anheim, Isabelle Arnulf, Solène Ansquer, Jean-Philippe Brandel, Christine Brefel-Courbon, Luc Defebvre, Sophie Drapier, Alexandre Eusebsio, Margherita Fabbri, Caroline Giordana, Elodie Hainque, Stephane Lehericy, Ana Marques, Caroline Moreau, Elena Moro, Fabienne Ory, Anne-Sophie Rolland, Stéphane Thobois, Marie Vidailhet, David Devos, Louise-Laure Mariani, Suzanne Lesage, Alexis Brice, Jean-Christophe Corvol, for the Predistim study group, the Iceberg study group, the NSPark study group
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:npj Parkinson's Disease
Online Access:https://doi.org/10.1038/s41531-025-01060-6
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Summary:Abstract Bi-allelic pathogenic GBA1 variants cause Gaucher disease (GD), whereas certain heterozygous missense variants increase the risk of Parkinson’s disease (PD), although the underlying mechanisms are unclear. Here, we classified GBA1 missense variants using predictive and structural scores, and analysed their associations with enzyme activity, Saposin C (SapC) interaction and PD progression in 639 patients with heterozygous GBA1 variants from five cohorts. Principal component analysis (PCA) identified two components: PC1, associated with reduced β-glucocerebosidase activity, the GD clinical severity classification, younger age at PD diagnosis, and faster cognitive and motor decline; and PC2, associated with surface-exposed, flexible regions involved in SapC interactions, younger age at PD diagnosis, and slightly with motor decline. These findings highlight that impaired SapC interactions, in addition to reduced activity, may contribute to PD severity in GBA1 variant carriers. This is relevant for therapeutic approaches aimed at stabilizing β-glucocerebosidase or enhancing its enzymatic activity in PD.
ISSN:2373-8057

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