This project will validate the JAK/STAT pathway as a novel therapeutic strategy for treatment of Parkinson's Disease (PD), a neurodegenerative disease characterized by deterioration of motor activities that are controlled by the nigrostriatal system. PD results from progressive and selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. Additionally, PD brain is characterized by cytoplasmic and neuritic fibrillar ?-synuclein (?-syn) inclusions (Lewy bodies (LB) and Lewy neurites (LN), respectively). Recently, inflammation has been implicated as a major pathogenic factor in the onset and progression of PD. Cells of the immune system are involved in PD, including microglia (resident brain macrophage) and infiltrating macrophages and T-cells. In particular, microglia and macrophages polarized to the M1 pro- inflammatory phenotype are implicated in PD. The JAK/STAT pathway is the major signaling system used by cytokines, and is critical for development and regulation of immune responses. Dysregulation of the JAK/STAT pathway has pathological implications for autoimmune and neuroinflammatory diseases. We have documented hyperactivation of the JAK/STAT pathway in a ?-syn overexpression model of PD, and shown that use of a JAK inhibitor, AZD1480, attenuates microglial activation, T-cell infiltration and most importantly, neurodegeneration. We hypothesize that inappropriate activation of the JAK/STAT pathway causes dysregulation of innate and adaptive immunity, and that therapeutic intervention of this pathway will alter the progression of PD.
Aim 1. Involvement of the JAK/STAT Pathway in a ?-syn Preformed Fibril (sPFF) Model. We have recently demonstrated that sPFF enter neurons and recruit endogenous ?-syn to form LB/LN- like pathology, leading to neurodegeneration. Importantly, we have shown an inflammatory response that precedes neurodegeneration. This new model implicates propagation and cell-to-cell transmission of pathologic ?-syn as mechanisms for neurodegeneration, and possibly neuroinflammation. We will 1) discover whether activation of the JAK/STAT pathway is involved in the spread and propagation of pathologic ?-syn and 2) determine if JAK inhibitors suppress both neuroinflammation and neurodegeneration in this model.
Aim 2. Susceptibility of M1-polarized Mice to Models of Synucleinopathy. In this aim, we take a different approach, which is to ask how PD pathogenesis is affected in the setting of JAK/STAT hyperactivation. We have a mouse model in which myeloid cells are polarized to the M1 pro-inflammatory phenotype, and display heightened activation of the JAK/STAT pathway. Using two models of synucleinopathy (overexpressed ?-syn and sPFF), we will assess if activation of the JAK/STAT pathway and M1 polarization promotes more severe pathology, including neuroinflammation and degeneration of DA neurons. The proposed studies address an unanswered question in PD: is JAK/STAT signaling an important factor in the onset and progression of PD?
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|Harms, Ashley S; Thome, Aaron D; Yan, Zhaoqi et al. (2018) Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease. Exp Neurol 300:179-187|
|Abdelmotilib, Hisham; Maltbie, Tyler; Delic, Vedad et al. (2017) ?-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic Neurodegeneration. Neurobiol Dis 105:84-98|
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|Harms, Ashley S; Delic, Vedad; Thome, Aaron D et al. (2017) ?-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration. Acta Neuropathol Commun 5:85|
|West, Andrew B (2017) Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp Neurol 298:236-245|
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|Ponnazhagan, Ranjani; Harms, Ashley S; Thome, Aaron D et al. (2016) The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia. J Neuroimmune Pharmacol 11:231-7|
|Litvan, Irene; Lees, Peter S J; Cunningham, Christopher R et al. (2016) Environmental and occupational risk factors for progressive supranuclear palsy: Case-control study. Mov Disord 31:644-52|
|West, Andrew B; Cookson, Mark R (2016) Identification of bona-fide LRRK2 kinase substrates. Mov Disord 31:1140-1|
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