Glia maturation factor dependent mast cell activation in Parkinson's disease

Iowa City Va Medical Center, Iowa City IA

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Abstract

DESCRIPTION (provided by applicant): 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.