Mutations in the LRRK2 gene are the greatest known contributors to genetic forms of Parkinson’s disease (PD). This project will investigate whether LRRK2 function also plays a role in the more common, non-genetic (or sporadic) forms of PD. We will analyze LRRK2 function in nerve cells that will be generated from induced pluripotent stem cells (iPSCs) derived from sporadic PD patients.
iPSCs from patients with sporadic PD and from control individuals will be turned in vitro into dopamine-producing nerve cells using a cocktail of growth factors. Specific changes recently found in neurons with mutated LRRK2 function will be compared in cells from sporadic PD patients with those from control individuals. These changes comprise higher sensitivity against oxidative stress, outgrowth of neuronal processes, and the level and specific state of certain cellular proteins. Furthermore, the response of these changes on specific LRRK2 inhibitors will be investigated.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Genetic forms of PD are quite rare, but analyzing the pathogenic functions of PD-associated genes such as LRRK2 is expected to uncover mechanisms relevant also for non-genetic forms of PD. However, initial experiments are required that investigate whether LRRK2 specific alterations are also present in non-genetic forms of PD. Results from this analysis could provide information about disturbed pathways that PD patients with or without LRRK2 mutations have in common, and such pathways could then be targets for new medications.
A potential outcome of this study could be the discovery of a LRRK2-mediated pathomechanism in non-genetic forms of Parkinson’s disease, which would be a very encouraging finding. Results from this study could provide potential targets for medication that are not only relevant for patients with a LRRK2 mutation but also for patients with sporadic PD. Additionally, if LRRK2 function proves to be implicated in sporadic PD, further investigations can analyze more LRRK2-associated mechanisms in sporadic PD.