Variants of the LRRK2 gene are associated with overactivation of the LRRK2 protein’s activity and an increased risk of Parkinson's disease (PD). We have previously demonstrated LRRK2-related changes in fibroblasts (a kind of cell) derived from the skin of PD patients carrying LRRK2 genetic mutations. We hypothesize that fibroblasts from PD patients without a LRRK2 mutation (idiopathic PD or iPD) will show similar changes and may be sensitive to rescue by LRRK2 inhibitors.
We will use our reliable cellular assays (experiment set-ups) to determine the role of LRRK2 in human fibroblasts from patients with iPD and age-matched controls. Specifically, we will (a) determine whether iPD human fibroblasts are metabolically different than normal control fibroblasts; (b) establish the vulnerability of iPD human fibroblasts to cell toxins and stressors that model cell dysfunction; and (c) determine if pharmacological LRRK2 inhibitors can rescue the vulnerabilities of iPD fibroblasts.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
These studies will establish the contribution of normal LRRK2 function in mediating cell biological processes in iPD patient derived cells. This project will potentially pave the way for new treatments.
Inhibitors of LRRK2 are under development for use in the clinic for LRRK2-associated parkinsonism. The experiments will provide important information on LRRK2-associated mechanisms in people with Parkinson’s but without a LRRK2 mutation. We believe that fibroblasts from patients with iPD will (1) exhibit similar cellular vulnerabilities as patients with LRRK2 mutations and (2) may be sensitive to rescue by LRRK2 kinase inhibitors.