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.

Public Health Relevance

Parkinson's disease is one of the most prevalent and progressive neurological diseases that affects both genders and over 1 million Americans suffer from PD;approximately 40% of the victims are under the age of 60, and the lack of effective treatments for PD represents a significant gap in the ability to treat this devastating disease. Based on glia maturation factor's (GMF) ability to induce several well-established pro-inflammatory mediators, we hypothesize that GMF is involved in the pathogenesis of PD. The aim of this proposal is to elucidate GMF as a novel candidate for therapeutic intervention in PD;therefore, these studies may provide the scientific rationale for the development of a novel non-toxic therapy for PD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Sieber, Beth-Anne
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University of Iowa
Schools of Medicine
Iowa City
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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
Kempuraj, Duraisamy; Thangavel, Ramasamy; Selvakumar, Gvindhasamy Pushpavathi et al. (2018) Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-?B. Mol Neurobiol :
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
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
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, 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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