Mutations in LRRK2 cause the most common familial forms, and some sporadic forms, of Parkinson’s disease. Considerable evidence indicates that the neurotoxicity of these LRRK2 mutations correlates with hyperactivation of LRRK2's kinase activity. Understanding which structural mechanisms drive kinase hyperactivation and how to modulate and inhibit LRRK2 GTPase and kinase activities is pivotal for unraveling the disease mechanisms and developing the future therapeutic strategies.
We will (1) screen and identify chemical probes that modulate LRRK2 kinase and GTPase activities; (2) study the structural mechanism underlying PD-linked aberrant enzymatic activity of LRRK2; (3) investigate LRRK2 domain-specificity of selected compounds and domain interactions; and (4) elucidate the crystal structure of the GTPase and kinase domains in complex with selected compounds.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our ability to utilize brain-specific, full-length LRRK2 protein offers a unique opportunity to study LRRK2 function/structure under physiological conditions and will facilitate drug target validation and development. The structural insight through this study will reveal how these compounds modulate the activity of these domains and provide a basis for future optimization of their inhibitory properties.
Our study not only will provide new structural and mechanistic insight into the function and regulation of LRRK2 in PD, but also generate specific chemical probes that can be used as research tools for PD research and as a basis for the future development of PD drugs. Therefore, we strongly believe that the outcome of our research will greatly benefit the PD research community at large.