The overarching goal of this renewal R01 is to advance our understanding of the biology and pathology of Leucine-Rich Repeat Kinase 2 (LRRK2), whose mutations are the most common genetic cause of Parkinson's disease (PD). LRRK2 encodes a large and complex protein (285kD) including a kinase and a GTPase domain. Previously multiple lines of evidence have led to a """"""""gain-of-function"""""""" hypothesis that LRRK2 pathogenic mutations cause increased kinase activity that is attributable to the neurotoxicity. Recent studies in cell cultures implicate LRRK2 in vesicle trafficking, neurite outgrowth, cytoskeletal dynamics, protein translation and degradation, mitochondria dynamics and inflammatory response. Importantly, the study of genetic animal models show that the pathogenic LRRK2 mutations impair dopamine transmission without causing neurodegeneration, suggesting a pathophysiological role of LRRK2 in neurotransmission at early disease stage prior to neurodegeneration. Emerging evidence has also linked LRRK2 to neuroinflammation that is a contributing factor to neurodegeneration in PD. But the precise mechanisms whereby LRRK2 mutant mediate the neural dysfunction and neurotoxicity remain unclear. Therefore, we hypothesize that (1) LRRK2 regulates SV protein functions and neurotransmission that is impaired by LRRK2 pathogenic mutations;2) LRRK2 plays a critical role in neuroinflammatory response in glial cells;LRRK2 mutants deregulate glial inflammatory pathway and cause neurotoxicity in PD.
Our specific aims are to (1) determine the pathogenic role of LRRK2 in SV traffic and neurotransmission;(2) examine dysfunctional LRRK2 in glial neuroinflammatory response. A major challenge of LRRK2 research is the lack of well-defined neurodegeneration models of LRRK2 that are relevant to the PD pathogenesis. In fact, the incomplete disease penetrance of the common mutation G2019S suggests a significant contribution of environmental factors to PD pathogenesis.
Our third aim i s then to test the hypothesis in animal models that LRRK2 causes neurodegeneration in PD through genetic lesion and environmental toxin-linked neuroinflammation. Successful completion of the study not only will gain insight into LRRK2 biology and pathophysiology, but also will deliver valuable cell and animal models for interrogating neurodegenerative pathways in PD and developing platforms for LRRK2 inhibitor screening.
Our application will investigate potential pathogenic pathways mediated by LRRK2 in Parkinson's disease. We seek to develop two-hit LRRK2 neurodegeneration model for PD by combining LRRK2 genetic lesions and environmental toxin exposure. If successful, our study not only will gain insight into molecular and cellular mechanism for the pathogenesis of PD, but also will establish valuable cell and animal models for developing therapeutic strategies to treat PD.
|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|
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|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|
|Yang, Yi; Coleman, Michael; Zhang, Lihui et al. (2013) Autophagy in axonal and dendritic degeneration. Trends Neurosci 36:418-28|
|Dehay, Benjamin; Martinez-Vicente, Marta; Caldwell, Guy A et al. (2013) Lysosomal impairment in Parkinson's disease. Mov Disord 28:725-32|
|Sepulveda, Bryan; Mesias, Roxana; Li, Xianting et al. (2013) Short- and long-term effects of LRRK2 on axon and dendrite growth. PLoS One 8:e61986|
|Bezard, Erwan; Yue, Zhenyu; Kirik, Deniz et al. (2013) Animal models of Parkinson's disease: limits and relevance to neuroprotection studies. Mov Disord 28:61-70|
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