Role of LRRK2 in Alpha-synuclein-induced Neurodegeneration: Supplement

Promising Outcomes of Original Grant:
We seek to develop a robust and standardized pre-clinical model relevant to late-onset Parkinson’s disease (PD) that will identify clinically viable LRRK2 kinase inhibitors for the treatment of PD. Previously, we have found that LRRK2 knockout models are protected from rAAV2 alpha-synuclein-induced dopaminergic neurodegeneration, and that Pfizer A drug administration (a clinically viable LRRK2 kinase inhibitor) also provides protection from alpha-synuclein-induced dopaminergic neurodegeneration.

Objectives for Supplemental Investigation:           
In this supplement, we will test whether G2019S-LRRK2 transgenic models are more sensitive to alpha-synuclein-induced dopaminergic degeneration, and if so, whether this can be reduced by Pfizer A administration. The effects of long-term administration of Pfizer A will be evaluated in organs and cells known to express high levels of LRRK2. Many companies and institutes have identified possible LRRK2 inhibitors that have the potential to advance to clinical trial, but pre-clinical models with face-validity to late-onset PD poise large technical challenges that hinder their ability to resolve the best compounds. The final goal is to evaluate possible pathologies arising from long-term usage of the Pfizer A inhibitor.

Importance of This Research for the Development of a New PD Therapy:      
It is known that individuals with the G2019S-LRRK2 mutation are at particular risk for late-onset PD. LRRK2 inhibitors may particularly benefit individuals with the G2019S-LRRK2 mutation, Here, we test a historically efficacious platform, namely rAAV2-alpha-synuclein viral induction in models, in the context of G2019S-LRRK2 over-expression and PfizerA drug administration. Potential liabilities due to LRRK2 long-term inhibition through small molecules will also be identified.