Mitochondrial Homeostasis and LRRK2 Parkinsonism: Novel Neuroprotection Targets

Objective/Rationale:             
The genes related to familial forms of Parkinson’s disease (PD) have been associated with alterations of normal mitochondrial integrity and function. Little is known to date about how LRRK2 acts on pathways controlling mitochondrial homeostasis. This project aims to develop a cellular signature of LRRK2 parkinsonism that may be capable of informing and translating effective therapeutics targeting LRRK2.

Project Description:             
We will compare cell cultures derived from patients with a LRRK2 mutation (LRRK2+) to cultures from sporadic PD patients (cause unknown) and control subjects. We will also study dopaminergic neurons derived from induced pluripotent stem cells. Finally, we will test the disease-modifying property of Pfizer LRRK2 inhibitors on the novel cell models produced. Our objective is to validate the cell model produced and to quantify the percentage of neuroprotection conferred by the drugs in LRRK2+ PD patients, thus understanding better the basis for drug-response in this patient group.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
We will improve biological understanding of LRRK2 function and PD-associated mitochondrial dysfunction to inform effective therapeutic targeting of LRRK2.

Anticipated Outcome:          
Our project will generate cell signatures that are associated with LRRK2 parkinsonism, leading to models for the selection of disease-modifying drugs targeted to LRKK2+ patients and to patient stratification in clinical trials.