The LRRK2 protein undergoes chemical modification called phosphorylation, which can alter its function, and is carried out by enzymes called kinases (LRRK2 is also a kinase). Phosphorylation of LRRK2 by kinases is disrupted in several Parkinson's disease (PD)-causing mutations in LRRK2 and LRRK2 activity is blocked with small molecule inhibitors, linking the regulation of LRRK2 to PD. We can understand more about the pathology of LRRK2 PD-causing mutations and the effects of inhibiting LRRK2, a potential PD therapeutic, if we can identify and characterize the kinases that mediate LRRK2 phosphorylation. This study will follow genetic and biochemical evidence to characterize a kinase that regulates LRRK2, called TNIK (TRAF2 and NIK interacting kinase).
Based on our genetic and biochemical preliminary data, we hypothesize that the TNIK kinase phosphorylates LRRK2.
Our first goal is to understand how LRRK2 and TNIK interact with each other in normal and pathogenic conditions. We will ask if a novel and rare TNIK PD mutant changes the phosphorylation or binding of LRRK2 and if LRRK2 is involved in some of the known functions of TNIK biology. Finally, we will correlate LRRK2 expression and phosphorylation with TNIK protein levels in samples from the Parkinson's Institute Brain Bank.
Impact on Diagnosis/Treatment of Parkinson's disease:
Identification of new signaling pathways that feed into LRRK2 brings a better understanding of targeting LRRK2 as a therapeutic target. It is also important to identify new potential pathways that overlap with known genetic causes of PD as new targets for pharmacological modulation.
Next Steps for Development:
The proteins that regulate the phosphorylation of LRRK2 are novel signaling nodes that impact the function of a relevant PD therapeutic target, in turn opening our understanding of new inputs into PD pathology that can be considered new targets for therapeutic intervention. Furthermore, a full understanding of the role that LRRK2 plays in genetic and idiopathic (no known cause) PD has yet to be fully realized. Therefore, broadening our knowledge of the regulatory networks that may be disrupted in PD could advance current and future preventative or disease-modifying therapies.