Our long-term goal is to understand the cellular and molecular basis for the initial pathogenic events of Parkinson's disease (PD), such as dopamine (DA) deficiency and aberrant synaptic activity that precedes and contributes to abnormalities in movement, learning and emotion. Using a BAC transgenic approach, we have previously investigated normal and pathophysiological functions of Leucine-rich-repeat-kinase 2 (LRRK2), a newly identified causative gene for familial PD, in mouse models. We have recently reported that LRRK2 is involved in regulating striatal DA transmission and consequent control of motor function. The LRRK2 mutation G2019S, which is the single most common genetic cause of PD, exerts pathogenic effects by impairing these functions of LRRK2. The emerging evidence thus suggests that this LRRK2 PD-linked mutation can initiate a series of pathological events (including the impairment of striatal DA transmission) at an early phase of PD preceding nigrostriatal degeneration. Our preliminary study has shown that LRRK2-G2019S causes aberrant synaptic plasticity in the striatum and hippocampus of our LRRK2 BAC transgenics. Therefore, these results suggest that LRRK2-G2019S triggers the deregulation of multiple neural pathogenic pathways that are consistent with abnormalities in both motor and cognitive deficits in PD. Furthermore, we found that brain LRRK2-G2019S has enhanced kinase activity, and in mouse brain LRRK2 kinase is responsible for the phosphorylation of Erzin/Radixin/Moesin (ERM), an event that is associated with spine morphogenesis. We hypothesize that the pathogenic role of LRRK2 is at both presynaptic and postsynaptic sites: (1) LRRK2 regulates DA homeostasis/transmission, whereas the G2019S mutation impairs DA transmission and causes DA deficiency;(2) LRRK2-G2019S triggers deregulation of multiple neural circuits implicated in clinical manifestations of motor, cognitive and psychiatric symptoms of PD;(3) Some pathological consequences of PD are caused by a combination of DA transmission deficits and postsynaptic abnormalities. Hence, we plan to test these hypotheses in our established BAC transgenic mice expressing LRRK2 variants:
Aim 1 : Determine cellular and molecular mechanisms through which LRRK2 regulates dopamine transmission that is impaired the PD-linked mutation G2019S;
Aim 2 : Analyze the pathogenic effects of LRRK2 in the electrophysiology of striatum and hippocampus;
Aim 3 : Analyze the pathogenic effects of LRRK2 in dendritic morphology and its plasticity;
Aim 4 : Determine whether LRRK2 transgenic mice develop cognitive deficits and dopamine-related motor abnormalities. The outcome of this study is expected to shed light on the pathogenic mechanism underlying the motor and non-motor symptoms of PD, and reveal causative molecular events at an initial stage of PD that are critical for biomarker identification, early diagnostics and therapeutic intervention.
The proposed research plan is expected to elucidate the pathogenic mechanism underlying the motor and cognitive symptoms of Parkinson's disease, and reveal causative molecular events at an initial stage of Parkinson's disease that are critical for biomarker identification, early diagnostics and therapeutic intervention.
|Travaglia, Alessio; Bisaz, Reto; Sweet, Eric S et al. (2016) Infantile amnesia reflects a developmental critical period for hippocampal learning. Nat Neurosci 19:1225-33|
|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|
|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|
|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|
|Friedman, Lauren G; Lachenmayer, M Lenard; Wang, Jing et al. (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of ?-synuclein and LRRK2 in the brain. J Neurosci 32:7585-93|
|Yue, Zhenyu (2012) Genetic mouse models for understanding LRRK2 biology, pathology and pre-clinical application. Parkinsonism Relat Disord 18 Suppl 1:S180-2|
|Yue, Zhenyu; Lachenmayer, M Lenard (2011) Genetic LRRK2 models of Parkinson's disease: Dissecting the pathogenic pathway and exploring clinical applications. Mov Disord 26:1386-97|