Mutations in the GBA gene are probably the most common genetic cause of Parkinson's disease (PD), and the second most important cause for dementia with Lewy bodies (DLB, after the APOE e4 allele). Mutations in GBA account for up to 20% of patients with PD in different populations (5-20% in most populations) and up to 30% of DLB patients in different populations (5-30%). The association of GBA mutations with multiple system atrophy (MSA) is not clear, as some studies showed no association between GBA mutations and MSA, while the largest study so far demonstrated a strong association, albeit weaker than the association with PD or DLB. As expected, GBA mutations are responsible for 10-15% of RBD patients in different populations (the association was not examined in the population in which these mutations are the most common, the Ashkenazi Jewish population).
Severe and mild GBA mutations (as determined by their role in type I (mild), type II or type III (severe) Gaucher's disease) differentially affect the clinical presentation and progression of PD. The age at onset is younger among severe GBA mutation carriers, and they progress and develop dementia faster.
Interestingly, the enzymatic activity of Glucocerebrosidase (GCase) is lower in the brain and blood of PD patients even without GBA mutations, suggesting that this enzyme may have a central role also in sporadic PD.
GBA is a main focus of our lab, and we are involved in a large variaty of GBA research, from basic science to clinical trials. Ongoing GBA-related projects:
Phase 2 clinical trial for a substrate reduction therapy for PD patients with GBA mutations (Sanofi/Genzyme).
Identification of genetic modifiers of GBA associated PD from GWAS and targeted NGS data.
Effects of GBA mutations / reduced activity on the lysosome and internalization and degradation of alpha synuclein.
Design of a specific biomarker for GBA-associated PD.
Developing new targeted NGS method for GBA sequencing (with Cergentis).
GBA enzymatic activity in RBD and PD-MCI
GBA mutations and conversion to PD, DLB and MSA from RBD.
Click on paper for PubMed link