Parkinson disease (PD) due to monoallelic glucocerebrosidase (GBA1) gene mutations (GBA-PD) is at the forefront of novel approaches to the treatment of PD. Exciting potential therapeutic agents that target the pathway disrupted in this genetic form of PD are becoming available, and evidence suggests that benefits extend to non-mutation PD, as well. Trial development is at a pivotal stage. Demonstration of effects in trials of potential disease-modifying agents for PD in general has been impeded by uncertainty about disease etiology, heterogeneity of underlying mechanisms, few identified targets, few sensitive and stable outcome measures (especially for non-motor outcomes), and insufficient surrogate markers.
This proposal aims to determine the relationship between markers of glucocerebrosidase function and particularly, whether excess sphingolipids are associated with the clinical features and progression of Parkinson disease.
GBA1 mutations cause deficiency in the lysosomal glucocerebrosidase enzyme (GCase) and are the most common genetic factor associated with PD. Utilizing longitudinal data from our site, Mount Sinai Beth Israel (MSBI), the MJFF LRRK2 Consortium and the BioFind study, the Harvard Biomarker Study (HBS), the Parkinson's Disease Biomarkers Program (PDBP), the study represents one of the larger clinical and biological biomarker studies focusing on the role of GCase in PD. We propose to characterize focused biochemical measures of the GCase pathway, including central and peripheral assessments of GCase, levels of GCase lipid substrates and α-synuclein and their relation to clinical outcomes and decline in GBA-PD, idiopathicPD (IPD) and controls.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This study presents an opportunity to characterize the progression of markers in GBA-PD over time and identify markers of target engagement for clinical trials of new PD therapies-- some of which are currently in development.
Next Steps for Development:
Evaluation of biochemical markers in this pathway in conjunction with clinical motor and non-motor features will provide outcome measures for clinical trials. Further, disruption of the GCase pathway may be an important representative mechanism for non-mutation, idiopathic PD (IPD), and has been implicated as a possible etiology in at least a subset of IPD.