PR002623 (Project)

Description:Variants in GBA1 cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson’s disease (PD). While some GBA1 variants are associated with both GD and PD, several coding mutations, including E326K, specifically confer risk for PD. The impact of these PD-specific variants on GCase activity and lysosomal and mitochondrial function relevant to PD remains poorly understood. We show the E326K variant reduces lysosomal GCase activity by impairing its delivery to lysosomes via altered interactions with its receptor, LIMP2. Structural analyses reveal that loss of a key salt bridge between E326 and R329 underlies disrupted GCase/LIMP2 interaction in cells, as reintroduction of a negative charge at R329 rescues LIMP2 binding. Functionally, the E326K variant produces greater deficits in PD-relevant pathways than GD-linked severe GCase LoF with effects reproduced in CNS cells and human E326K carriers, providing key insights into the nature of GCase dysfunction associated with GBA1-PD.