Objective/Rationale:
The LRRK2 kinase enzyme is mutated in some patients with Parkinson’s disease (PD). Coincidentally, the kinase is widely expressed in most organs of the body. We examined various pre-clinical models with LRRK2 either absent or mutated and found a severely disturbed phosphate and vitamin D3 metabolism. The major aim of this project is to examine the role of LRRK2 in the regulation of systemic and local vitamin D3 metabolism and vitamin D3-dependent gene regulation.
Project Description:
We will examine: 1) the regulation of vitamin D3-metabolizing enzymes in human cell lines including cell lines derived from PD patients with LRRK2 mutations, 2) the regulation of LRRK2 expression by vitamin D3 in human cell lines as well as in pre-clinical models, and 3) measurement of vitamin D3 and other phosphate-regulating hormones in patients with LRRK2 mutations as well as in healthy controls. The project combines in vivo experiments in LRRK2 pre-clinical models and in various human cell lines and human samples from various organs from patients with PD and LRRK2 mutations.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our data may establish vitamin D3 as a novel marker of disease progression as well as a new target for (adjuvant) therapy of LRRK2-dependent PD.
Anticipated Outcome:
We will decipher the role of LRRK2 in the regulation of systemic and local vitamin D3 levels and understand how vitamin D3 regulates LRRK2. We will also measure vitamin D3 levels in affected patients.