Parkinson's disease (PD) is a chronic and progressive movement disorder characterized by the degeneration of dopaminergic neurons and presence of Lewy body. Clinically, PD is characterized by resting tremor, rigidity, bradykinesia and postural instability. Inflammatory responses manifested by glia, T cell infiltration, and increased expression of inflammatory toxic mediators in the glial and neuronal cells, are prominent features of PD. Neuroinflammation is an important contributor to the pathogenesis of PD and may further augment progressive loss of nigral dopaminergic neurons. Approximately one million Americans are living with PD. At present, the annual combined direct and indirect cost of healthcare for PD patients is estimated to be nearly $25 billion in the USA. However, the etiology of PD remains unknown; and though there is currently no cure, but there are treatment options available such as medication and surgery to manage its symptoms. The lack of treatments for the progressive phase of PD represents a significant gap in the clinician's ability to treat this disease. The goal of this proposal is to study the role of glia maturation factor (GMF), a novel protein first discovered in our laboratory at the University of Iowa, in the activation of mast cells and secretion of proinflammatory mediators that are responsible for neurodegeneration in the pathogenesis of PD. Emerging evidence suggests glia-neuron-mast cell communications in neuroinflammatory conditions. We hypothesize that GMF-dependent activation of mast cell is associated with the pathophysiology of PD. We will elucidate the regulatory role of GMF in degeneration of neurons in order to provide a mechanistic basis for GMF-mediated pathogenesis in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) mouse model of PD. We will examine whether GMF is required in human and mouse primary mast cell activation and secretion of proinflammatory cytokines/chemokines and free radical that are responsible for degeneration of dopaminergic neurons following parkinsonian toxin 1-methyl-4- phenyl-pyridinium ion (MPP+) treatment in in vitro studies. We will analyze the mechanistic pathways involved in the activation of mast cells by GMF. Next, we will investigate if GMF exerts its effects by modulating mast cells in degeneration of nigrostriatal dopaminergic neurons in mouse models of PD. For this purpose we will use both MPTP-induced acute and chronic mouse models. We will reconstitute mast cell deficient (W/Wv) mice with bone marrow-derived mast cells from GMF-deficient (GMFKO) mice or Wild type mice and challenge with MPTP. We will analyze MPTP-induced neuroinflammation, neurochemical deficits, nigrostriatal degeneration, and correlate with behavioral parameters in these animal models. The present study has significant clinical implications, and provides an efficient in vivo approach to test GMF- suppression strategies as therapeutic agents for neurodegenerative diseases, including PD.

Public Health Relevance

Parkinson's disease (PD) is a serious health problem in the United States and approximately one million Americans and estimated 80,000 Veterans are living with PD. The relevance of this research to Veterans health is that it could identify new therapeutic strategies to combat neurodegenerative diseases, including PD and Alzheimer's disease. The lack of effective treatments represents a significant gap in the ability to treat these devastating neurodegenerative diseases, and therefore the study of the role of glia maturation factor in the activation of glia-mast cell-neuron axis and secretion of proinflammatory mediators that are responsible for neurodegeneration may provide the scientific rationale for the development of novel therapy for these devastating illnesses.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002477-02
Application #
8962063
Study Section
Neurobiology E (NURE)
Project Start
2014-10-01
Project End
2018-09-30
Budget Start
2015-10-01
Budget End
2016-09-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Thangavel, Ramasamy; Bhagavan, Sachin M; Ramaswamy, Swathi Beladakere et al. (2018) Co-Expression of Glia Maturation Factor and Apolipoprotein E4 in Alzheimer's Disease Brain. J Alzheimers Dis 61:553-560
Kempuraj, Duraisamy; Selvakumar, Govindhasamy Pushpavathi; Zaheer, Smita et al. (2018) Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson's Disease. J Neuroimmune Pharmacol 13:100-112
Selvakumar, Govindhasamy Pushpavathi; Iyer, Shankar S; Kempuraj, Duraisamy et al. (2018) Glia Maturation Factor Dependent Inhibition of Mitochondrial PGC-1? Triggers Oxidative Stress-Mediated Apoptosis in N27 Rat Dopaminergic Neuronal Cells. Mol Neurobiol 55:7132-7152
Ahmed, Mohammad Ejaz; Iyer, Shankar; Thangavel, Ramasamy et al. (2017) Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer's Disease Brain. J Alzheimers Dis 60:1143-1160
Kempuraj, Duraisamy; Thangavel, Ramasamy; Selvakumar, Govindhasamy P et al. (2017) Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration. Front Cell Neurosci 11:216
Kempuraj, Duraisamy; Caraffa, Alessandro; Ronconi, Gianpaolo et al. (2016) Are mast cells important in diabetes? Pol J Pathol 67:199-206
Kempuraj, D; Thangavel, R; Natteru, P A et al. (2016) Neuroinflammation Induces Neurodegeneration. J Neurol Neurosurg Spine 1:
Kempuraj, Duraisamy; Thangavel, Ramasamy; Fattal, Ranan et al. (2016) Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4-Phenyl-Pyridinium (MPP(+)). Neurochem Res 41:1042-9
Kempuraj, Duraisamy; Thangavel, Ramasamy; Yang, Evert et al. (2015) Dopaminergic Toxin 1-Methyl-4-Phenylpyridinium, Proteins ?-Synuclein and Glia Maturation Factor Activate Mast Cells and Release Inflammatory Mediators. PLoS One 10:e0135776
Khan, Mohammad Moshahid; Zaheer, Smita; Thangavel, Ramasamy et al. (2015) Absence of glia maturation factor protects dopaminergic neurons and improves motor behavior in mouse model of parkinsonism. Neurochem Res 40:980-90

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