Objective/Rationale:
Clinical and genetic findings have established a clear link between the LRRR2 gene and Parkinson’s disease. To what extent and by what mechanisms LRRK2 contributes to sporadic disease (cause unknown) remains unknown. One hypothesis is that increased LRRK2 protein (genes encode proteins) activity is involved in the disease process. By identifying cellular fingerprints specific to LRRK2 expression and activity in human blood cells, we aim to address these pending questions. Selected fingerprints will be evaluated in PD patients for their disease relevance and suitability as diagnostic and therapeutic biomarkers.
Project Description:
To identify LRRK2 specific fingerprints, we will perform analyses in peripheral blood mononuclear cells (PBMCs). By comparing PBMCs with different amounts of LRRK2 protein and/or different levels of LRRK2 activity, our first approach focuses on the identification of fingerprints linked to activity. Secondly, PBMCs isolated from human carriers of a LRRK2 genetic variant leading to familial PD will be compared to controls, thus underlining the disease aspect. Selected fingerprints will be evaluated in a larger PD patient cohort including both familial and sporadic cases.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This study will show to what extent LRRK2 plays a role in sporadic PD and assess whether patients with this type of the disease will benefit from specific treatments targeting LRRK2 biology (e.g. LRRK2 inhibitors). From a more general diagnostic and therapeutic standpoint, validated LRRK2 fingerprints will serve as biomarkers and help identify subjects at risk even before disease onset, thus allowing for early therapeutic evaluation.
Anticipated Outcome:
The identification of biological LRRK2 fingerprints will shed light on LRRK2 cellular function(s) and associated signaling pathways. The outcome of this study will also help identify novel/alternative treatment targets for both LRRK2 familial and sporadic PD.