GMF-dependent neuroinflammation and neurodegeneration

University Of Iowa, Iowa City IA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Parkinson's disease is progressive disabling and fatal. It is estimated that 60,000 new cases are diagnosed each year, joining the 1 million Americans who currently have Parkinson's disease, and there is no cure for this disease. PD is characterized by the presence of degenerating dopaminergic neurons, Lewy bodies and activated glia in brain. Although, the cause of PD is not clear, exposure to environmental neurotoxic pollutant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to be associated with the pathology of human PD and in animal models of PD. Invariably, activated glia are not only present but are also persistent in PD brains which could facilitate maintenance and progression of PD by secreting deleterious cytokines and chemokines. The glia maturation factor (GMF), discovered and characterized in our laboratory, is a conserved protein in mammalian brain/central nervous system. We already demonstrated the prominent role of GMF in activation of astrocytes and microglia by various factors and stimuli leading to death of neuronal cells. We hypothesize that GMF is also involved in pathogenesis of PD. This novel hypothesis is based on the demonstrated functions of GMF and our recent immuno-histological examinations that revealed numerous activated astrocytes, microglia and the prominence of GMF in nigrostriatal region of postmortem PD brains, as well as, in brains of experimental animal model of PD in which the changes in GMF, astrocytes and microglia preceded the loss of dopamine neurons. We forward three specific aims to support our hypothesis. Specific Aim 1 will examine the association between GMF and the pathology of PD. We will also examine whether GMF-dependent glial activation is required in the production of proinflammatory mediators that are responsible for degeneration of dopaminergic neurons. Specific Aim 2 will chart the comparative pathogenesis and progression of MPTP-induced dopaminergic neuronal loss in GMF-containing wild type and in GMF-deficient (GMF-KO) mice. We will compare the histopathological features, neurochemical changes, and behavioral motor deficits in Wt mice with GMF-KO mice. Specific Aim 3 will evaluate the suppression of neuroinflammation/neurodegeneration and therapeutic efficacy of our novel therapeutic approach of targeting GMF with GMF-specific siRNA to silence the GMF-signaling in MPTP-intoxicated mice.