Study Rationale: Sugars are added to proteins in a process called glycosylation. The precise manner in which these sugars are added is critical for the proper function of the resulting glycoproteins, and the cells in which they reside. New findings from our lab suggest that this process is severely affected in a genetic form of Parkinson’s disease (PD) that is associated with mutations in GBA1. In this study, we seek to validate these findings in stem-cell models and in blood samples collected from people with PD.
Hypothesis: We propose that altered protein glycosylation is a common feature of late-onset PD and that mutations in both GBA1 and LRRK2 will induce glycosylation defects. We further hypothesize that these changes will be evident in blood samples from people with sporadic and GBA1-associated forms of PD.
Study Design: We will examine brain cells and glia (astrocytes) derived from the stem cells of individuals carrying GBA1 or LRRK2 mutations and compare their protein glycosylation profiles to those of cells that are genetically identical but that do not carry disease-associated genetic variants. We will also study blood samples from healthy controls, individuals with sporadic PD, GBA1 carriers without PD and GBA1 carriers with PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: This study has the potential to identify a new feature of PD that may be traceable in blood samples. Having an easily accessible peripheral biomarker could facilitate monitoring of PD progression or serve as a tool for clinical trial initiation or evaluation.
Next Steps for Development: If successful, future work would include expansion into diverse sporadic PD populations, examination of other closely related movement disorders that may be distinguished by unique metabolic profiles (including progressive supranuclear palsy and multiple system atrophy) and standardization of assays across the field.