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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072359-04
Application #
8600733
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sieber, Beth-Anne
Project Start
2011-01-15
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$333,703
Indirect Cost
$136,828
Name
Icahn School of Medicine at Mount Sinai
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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