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

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.