A Novel Role for Glucocerebrosidase 1 (GBA1) in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, yet the pathological mechanisms driving disease onset and progression are not well understood. Glucocerebrosidase 1 (GBA1), the gene encoding the lysosomal enzyme glucoslyceramidase (GCase), has been identified as the most important genetic risk factor contributing to the development of PD. In this study, we aimed to investigate the relationship between inflammasome activation and GCase dysfunction in immune cells in PD. Primary microglial was generated from brains of P0‐ P2 mouse pups. After overnight serum cells was primed with 200 ng/mL of ultrapure LPS for 3 hr followed by treatment with either 40 µM of LTI‐291 or 200 µM of Condruitol β‐epoxide (CBE) for an hour. The cells was activated with 5 mM of adenosine triphosphate (ATP). The supernatant and cells were collected for IL‐1β and GBA assay, respectively. For in vivostudies, 8‐ 12 weeks old male C57BL/6J mice were injected with 20 μg of 6‐hydroxydopamine (6‐OHDA). Mice were treated with 12 mg/kg daily doses of LTI‐291 via oral gavage commencing 24 hours prior to surgery. On day 3 post‐surgery, brains were collected for analysis of protein expression. Our findings demonstrate that NLRP3 inflammasome activation increases IL‐1β production which significantly decreased in the presence of GCase activator, LTI‐291. This indicates the decreased inflammasome activation in conjunction with increased GCase activity. Similarly, GCase activity in LTI‐291 treated cells was significantly increased when compared to control and LPS primed samples. In vivo,6‐ OHDA mice had significant loss of tyrosine hydroxylase (TH), indicative of the substantial dopaminergic neuronal death which was rescued in LTI‐291 treated mice. Overall, these findings identify the potential role of NLRP3 inflammasome activation in driving GCase dysfunction, which could contribute to PD pathogenesis. Furthermore, we demonstrated that pharmacological augmentation of GCase activity was protective, reducing NLRP3 inflammasome activation in vitro and dopaminergic neuronal loss in vivo.