Recent studies have begun to underscore the importance of non cell-autonomous mechanisms contributing to neuronal dysfunction and death in neurodegenerative diseases such as Parkinson's Disease (PD). Neuroinflammation mediated by microglia is emerging as an important mechanism that promotes progression of PD. PD pathology is primarily characterized by two disease processes: the accumulation of misfolded aggregates of the protein ?-synuclein and degeneration of dopaminergic (DA) neurons in the substantia nigra. Interestingly, these disease processes are accompanied by significant increases in activated microglia that secrete pro-inflammatory cytokines and reactive toxic species. Modulating these inflammatory pathways in the brain may be an effective therapeutic strategy for PD. It has been shown that the lipid signaling molecule prostaglandin E2 (PGE2) can regulate innate immune responses in the brain via the pro- inflammatory receptor EP2 and anti-inflammatory receptor EP4. However, it is unclear how PGE2 mediated neuroinflammation interacts with Parkinsonian disease processes. The goal of this project is to investigate the role of pro- and anti-inflammatory PGE2 signaling in DA neurodegeneration and ?-synuclein aggregation in mouse models of Parkinsonism.
Aim 1 of this study will investigate the hypothesis that inhibiting microglial EP2 and EP4 signaling will modulate acute neurodegeneration in the MPTP neurotoxin induced model of DA cell loss. The Cre-loxP genetic strategy will be used to conditionally knockout EP2 and EP4 receptors in microglia. The production of neurotoxic factors by activated microglia such as reactive oxygen and nitrogen species (ROS/RNS) and the pro-inflammatory cytokine Interleukin-1? will be compared in cKO mice and controls. Furthermore, the effect of cKO of EP2 and EP4 on secondary neurotoxicity to DA neurons and motor behavior deficits will be determined.
Aim 2 will test the hypothesis that inhibiting EP2 signaling in the ?-synuclein overexpressing Thy1-A53T model of synucleinopathy will dampen the chronic inflammatory cycle and alter ?-synuclein aggregation and toxicity. Survival and motor behavioral phenotypes of Thy1-A53T;EP2-/- mice will be characterized. The correlation between microglial inflammatory activation and ?-synuclein aggregation at various stages of the disease course will be examined. The effect of EP2 deletion on neuronal dysfunction will be determined by measuring activity of the ubiquitin proteasome system and quantifying neuron loss in the spinal cord. The proposed experiments will provide novel insights into PGE2 mediated non cell-autonomous mechanisms underlying inflammation and neurodegeneration in PD. Identifying modifiers of PD pathogenesis would greatly aid in developing treatments for this complex neurodegenerative disorder.

Public Health Relevance

Parkinson's disease is a debilitating neurodegenerative disorder whose underlying cause is not known and whose disease course cannot be stopped by any existing treatment. Activation of microglial cells and associated neurotoxicity in brain regions of Parkinson's patients suggests that modulating neuroinflammation may be an effective therapeutic strategy for Parkinson's disease. The proposed research study will use the prostaglandin E2 signaling pathway as a tool to modulate inflammatory mechanisms and will examine the resulting effects on Parkinsonian disease processes.

Agency
National Institute of Health (NIH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS074712-03
Application #
8634818
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Pradhan, Suraj; Andreasson, Katrin (2013) Commentary: Progressive inflammation as a contributing factor to early development of Parkinson's disease. Exp Neurol 241:148-55
Johansson, Jenny U; Pradhan, Suraj; Lokteva, Ludmila A et al. (2013) Suppression of inflammation with conditional deletion of the prostaglandin E2 EP2 receptor in macrophages and brain microglia. J Neurosci 33:16016-32