The disease mechanism underlying Parkinson's disease (PD) is poorly understood. Mutations in LRRK2 (PARK8) have recently been linked to the most common familial forms (autosomal dominant) as well as some sporadic forms of Parkinson's disease (PD). LRRK2 protein contains multiple conserved domains including a kinase and a GTPase domain. Recent characterization of LRRK2 suggests that PD-associated mutations of LRRK2 cause enhanced kinase activity, which is linked to the neurotoxicity in neuron cultures. Our long-term goal is to elucidate the structure/function of LRRK2 in the CNS, to define the mutant LRRK2-mediated pathogenic pathways in PD, and to provide information for ultimate understanding of the pathogenesis of PD. The evidence that the pathology caused by familial PD gene mutations is restricted to the brain underscores the importance of brain-specific context in the onset and development of PD. Previously we have used an integrated system combining BAC (bacterial artificial chromosome)-mediated transgenic mice, proteomics and biochemical study to investigate the cellular function of LRRK2 in the context of brain. We have purified LRRK2 protein from the transgenic brain and found that the brain LRRK2 is associated with robust kinase and GTPase activity as compared to that from other tissues or cell cultures. Thus, we hypothesize that the kinase/GTPase activities of LRRK2 are specifically regulated by co-factors (e.g., proteins and lipids) in the brain. We will specifically test this hypothesis using purified LRRK2 from the brain (Aim 1). To further understand the regulation of LRRK2 enzymatic activity, we have identified phosphorylation sites in LRRK2 expressed in mouse brain. We have also developed an antibody against specific phosphorylation of LRRK2 to assist in the functional analysis of phospho- LRRK2. Since the levels of autophosphorylation of LRRK2 kinase are correlated with neurotoxicity, we propose to investigate the relationship between the identified phosphorylation and autophosphorylation in LRRK2, and to assess the functional significance of the identified phosphorylation of LRRK2 in LRRK2-mediated pathogenesis. In addition, we will test the hypothesis that specific phosphorylation of LRRK2 regulates LRRK2 kinase/GTPase activity and potentially modifies LRRK2-mediated pathological process in the brain (Aim 2). Finally, despite the recent evidence linking increased kinase activity and GTP binding of LRRK2 to neurotoxicity, the studies were performed mostly in cell cultures. In this application, we will use our BAC-mediated LRRK2 transgenic mice to validate these in vitro studies and further test the hypothesis of """"""""hyperactivity"""""""" of LRRK2 kinase in the pathogenesis of PD in vivo using animal models (Aim 3). By integrating biochemistry, cell biology and novel mouse transgenic approaches, our study is expected to provide mechanistic insight into the biology and pathology of LRRK2 protein, which is considered a promising drug target for the treatment of PD.
Parkinson's disease (PD) is a major human neurodegenerative disease, but the pathogenic mechanism is not clear. This application will investigate the central function of a PD-related gene and define the pathogenic pathway mediated by PD mutations of the gene in the central nervous system. It is expected to provide information for ultimate understanding of the etiology of PD and validation of drug targets for treatment of PD.
|Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:|
|Sheehan, Patricia; Yue, Zhenyu (2018) Deregulation of autophagy and vesicle trafficking in Parkinson's disease. Neurosci Lett :|
|Pan, Ping-Yue; Li, Xianting; Wang, Jing et al. (2017) Parkinson's Disease-Associated LRRK2 Hyperactive Kinase Mutant Disrupts Synaptic Vesicle Trafficking in Ventral Midbrain Neurons. J Neurosci 37:11366-11376|
|Sweet, Eric S; Saunier-Rebori, Bernadette; Yue, Zhenyu et al. (2015) The Parkinson's Disease-Associated Mutation LRRK2-G2019S Impairs Synaptic Plasticity in Mouse Hippocampus. J Neurosci 35:11190-5|
|Chikina, Maria D; Gerald, Christophe P; Li, Xianting et al. (2015) Low-variance RNAs identify Parkinson's disease molecular signature in blood. Mov Disord 30:813-21|
|Dusonchet, Julien; Li, Hu; Guillily, Maria et al. (2014) A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity. Hum Mol Genet 23:4887-905|
|Pan, Ping-Yue; Yue, Zhenyu (2014) Genetic causes of Parkinson's disease and their links to autophagy regulation. Parkinsonism Relat Disord 20 Suppl 1:S154-7|
|Krebs, Catharine E; Karkheiran, Siamak; Powell, James C et al. (2013) The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum Mutat 34:1200-7|
|Dehay, Benjamin; Martinez-Vicente, Marta; Caldwell, Guy A et al. (2013) Lysosomal impairment in Parkinson's disease. Mov Disord 28:725-32|
|Yang, Yi; Coleman, Michael; Zhang, Lihui et al. (2013) Autophagy in axonal and dendritic degeneration. Trends Neurosci 36:418-28|
Showing the most recent 10 out of 25 publications