Regulation of LRRK2 Activity by Nitric Oxide-Mediated Protein S-Nitrosylation

Objective/Rationale:
Mutations in the LRRK2 gene are a common cause of familial Parkinson’s disease (PD). Familial mutations can influence the GTPase or kinase activity of LRRK2 which may be important for the development of PD. How the enzymatic activity of LRRK2 is extrinsically regulated under normal or pathological conditions is not known. This project aims to explore the potential modification and novel regulation of LRRK2 by nitric oxide (NO)-mediated protein S-nitrosylation in cell and pre-clinical models.

Project Description:
LRRK2 exhibits low enzymatic activity under basal conditions and we hypothesize that oxidative and nitrosative stress may regulate the activation status of LRRK2 similar to members of the stress-activated mixed-lineage kinase family. Our preliminary data indicates that NO-mediated nitrosative stress can lead to the modification of LRRK2 by protein S-nitrosylation in pre-clinical cells, a process involving the reversible modification of cysteine residues with NO. Our studies will focus on exploring the S-nitrosylation of LRRK2 in cultured pre-clinical cells and neurons, as well as in PD-relevant brain tissues from human subjects and pre-clinical models. We further aim to explore the impact of S-nitrosylation on regulating the enzymatic activity of LRRK2. Our studies aim to elucidate a novel mechanism of regulation of LRRK2 activity by nitrosative stress.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
These studies will further our understanding of the molecular mechanisms that regulate LRRK2 activity in relevant model systems. LRRK2 has been implicated as a major cause of PD and is also associated with the more common idiopathic form of disease. This project may shed light on how non-mutated LRRK2 could contribute to idiopathic disease through increased nitrosative stress. These studies may eventually lead to the identification of new molecular targets for interfering with LRRK2-related neurodegeneration.

Anticipated Outcome:
This project will determine how extrinsic stress signals such as nitrosative stress can regulate the enzymatic activity of LRRK2 in pre-clinical cells and brain tissues. These studies may eventually identify new therapeutic strategies for targeting LRRK2 enzymatic activity and preventing neuronal damage.