Molecular regulation of LRRK2 in Parkinson's disease

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Parkinson's disease (PD) is recognized as the most common movement disorder. The cardinal symptoms of PD are caused by the progressive degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc) and accompanying striatal pathology. Mutations in LRRK2 are known to be the most common genetic causes of PD. Given its strong genetic links and compelling drug ability, LRRK2 represents a clear target for therapeutic development. However, the mechanisms that regulate LRRK2 function remain unclear. Moreover, LRRK2 regulation in striatal pathology and striatal-dependent behaviors remains largely elusive despite high expression of LRRK2 in the striatum. The LRRK2 protein includes two important enzymatic domains: a ROC (Ras of Complex) GTPase domain and a kinase domain. Disease causing mutations are found in both GTPase and kinase domains, indicating the importance of both GTPase and kinase activities of LRRK2. To date studies have focused largely on the kinase activity of LRRK2 while attention on the GTPase domain is limited. LRRK2 is a guanine nucleotide-binding protein, but the mechanism of direct regulation of its GTPase domain is unclear. Conventional guanine nucleotide-binding proteins are typically regulated by GTPase-activating proteins (GAPs) and guanine nucleotide-exchange factors (GEFs). Some guanine nucleotide-binding proteins can be activated by nucleotide-dependent dimerization (GAD). Whether LRRK2 is regulated by GAPs and GEFs or by GAD has been actively investigated. We have previously identified the first GAP ArfGAP1 for LRRK2 in vitro and in vivo. Recently we discovered a potential physiological GEF for LRRK2. It has similar expression patterns with LRRK2 in nigrostriatal pathway, interacts with LRRK2 and regulates LRRK2 neurotoxicity. Based on the preliminary observations, our central hypothesis is that this GEF serves as a physiological GEF for LRRK2 to increase LRRK2 GTP binding activity, regulate LRRK2 cellular function and LRRK2-induced striatal pathology and related behavioral deficits. The objective of this study is (1) to identify and characterize the first physiological GEF for LRRK2, (2) to determine how this GEF regulates LRRK2 function, and (3) to explore the regulation of this GEF on LRRK2 in striatal pathology and related behavior. Accomplishment of this study will lead to understanding how the GTPase function of LRRK2 is regulated and to determining whether this regulation affects the actions of LRRK2 in striatum. The LRRK2 GTPase, GAP or GEF activities would be served as new therapeutic targets, which is distinct from direct kinase inhibition of LRRK2. New knowledge regarding this aspect of LRRK2 biology will advance our understanding of the physiologic and pathophysiologic actions of LRRK2 as well as potential identification of novel targets for future pharmacologic intervention.