Study Rationale:
Mutations in the glucocerebrosidase (GBA) gene are among the most important risk factors for developing Parkinson´s disease. GBA activity is reduced in cerebrospinal fluid (CSF) of Parkinson’s patients independent of a GBA mutation. This indicates a general role of GBA in the development of Parkinson’s. To date, it is unclear whether reduced GBA activity in CSF results from a functional impairment of the enzyme or from reduced GBA protein concentration. Furthermore, GBA activity in CSF is a biomarker candidate for Parkinson’s. A validation of previous observations with a different method would strengthen these results.
Hypothesis:
The aim of our study is to measure GBA protein levels and GBA activity in CSF using an analytical lab technique called mass spectrometry. We want to confirm the previously described reduced GBA activity in Parkinson’s with mass spectrometry and uncover the origin of reduced GBA activity by measuring GBA protein levels.
Study Design:
We will establish the mass spectrometry methods for measurement of GBA activity and GBA protein levels in CSF using synthetic proteins and peptides. Using the mass spectrometry methods, we will analyze CSF of Parkinson’s patients and control volunteers from BioFIND, an observational study designed to discover and verify biomarkers of Parkinson's disease. These patients are well characterized in terms of GBA mutations and GBA activity and therefore ideally suited for this research.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
The GBA protein levels will give information about the origin of the reduced GBA activity in Parkinson’s, which is important to uncover the role of GBA in the development of the disease and for target identification in drug development. The combination of GBA protein level and activity in a ratio might improve the diagnostic power.
Next Steps for Development:
1) Adaption of the established methods by other labs and replication of the results in further and larger patient cohorts. 2) Comparison of changes in Parkinson’s with other neurodegenerative diseases. 3) Establishment of suitable assays for routine analysis.