LRRK2 dimerization and therapeutic evaluation

Johns Hopkins University, Baltimore MD

Investigators

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Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Currently, there is no proven neuroprotective therapy for PD and approaches for the identification of novel treatments are underdeveloped. Mutations in Leucine-rich repeat kinase-2 (LRRK2) are the most common known cause of Parkinson's disease (PD). LRRK2 is a large cytoplasmic protein (2527 aa) and contains both GTPase and kinase activities. Although efforts have been spent on developing LRRK2-targeted therapies, so far none of these are being utilized in a clinical setting. Thus, exploration and identification of novel therapeutic site(s) in the large LRRK2 protein may provide novel avenues for PD intervention. Recent studies suggest that the LRRK2 GTPase domain plays an important role in LRRK2 functions. PD-linked LRRK2 mutations within the GTPase domain alter either GTP binding or GTPase activity. Abolishing GTP binding by genetic alteration or pharmacological inhibition attenuates LRRK2 kinase activity and protects against neurodegeneration. Notably, the crystal structure of the LRRK2 GTPase domain shows it to be a dimer and biological studies suggest that LRRK2 may need to dimerize to act as a functional protein involved in cellular processes and neuronal growth. In this proposal, we propose to target the LRRK2 GTPase domain and identify dimerization inhibitors using computer-aided drug design (CADD) and biological screens. We will test the hypothesis that blocking LRRK2 dimerization by small molecules can attenuate LRRK2-induced neurodegeneration in LRRK2 cell and Drosophila models. These studies will validate whether blocking LRRK2 GTPase domain dimerization is a viable target for the development of novel therapeutic agents for PD intervention, and provide novel pharmacological tools for LRRK2-linked pathogenesis and therapeutic studies.