Lessons and future directions for GBA1-targeting therapies

In 2004, a study of 57 brains from individuals with Parkinson's disease was the first to show that heterozygous GBA1 variants could increase the risk of developing Parkinson's disease. 1 Lwin A Orvisky E Goker-Alpan O LaMarca ME Sidransky E Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab. 2004; 81: 70-73 Crossref PubMed Scopus (293) Google Scholar Since then, other studies have shown the role of GBA1 variants in different Parkinson's disease populations. 2 Gan-Or Z Amshalom I Kilarski LL et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology. 2015; 84: 880-887 Crossref PubMed Scopus (232) Google Scholar Additionally, efforts to study the cellular mechanisms underlying the association with GBA1 have generated different hypotheses on how gene variants might lead to Parkinson's disease. One prominent hypothesis was that reduced activity of glucocerebrosidase (the lysosomal enzyme encoded by GBA1) leads to accumulation of glucosylceramide, a glucocerebrosidase substrate. Glucosylceramide can interact with α-synuclein and increase its accumulation, and α-synuclein can then interact with glucocerebrosidase and prevent it from reaching the lysosome, creating a detrimental positive feedback loop. 3 Mazzulli JR Xu YH Sun Y et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011; 146: 37-52 Summary Full Text Full Text PDF PubMed Scopus (978) Google Scholar Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trialIn people with GBA1-associated Parkinson's disease in our study, venglustat had a satisfactory safety profile but showed no beneficial treatment effect compared with placebo. These findings indicate that glucosylceramide synthase inhibition with venglustat might not be a viable therapeutic approach for GBA1-associated Parkinson's disease. Full-Text PDF