1. Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration.
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Hongwei Qin, Buckley, Jessica A., Xinru Li, Yudong Liu, Fox III, Thomas H., Meares, Gordon P., Hao Yu, Zhaoqi Yan, Harms, Ashley S., Yufeng Li, Standaert, David G., and Benveniste, Etty N.
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JAK-STAT pathway ,SYNUCLEINS ,DOPAMINERGIC neurons ,RISK factors of neurodegeneration - Abstract
Parkinson's Disease (PD) is an age-related, chronic neurodegenerative disorder. At present, there are no disease-modifying therapies to prevent PD progression. Activated microglia and neuroinflammation are associated with the pathogenesis and progression of PD. Accumulation of α-synuclein (α-SYN) in the brain is a core feature of PD and leads to microglial activation, inflammatory cytokine/chemokine production, and ultimately to neurodegeneration. Given the importance of the JAK/STAT pathway in activating microglia and inducing cytokine/chemokine expression, we investigated the therapeutic potential of inhibiting the JAK/STAT pathway using the JAK1/2 inhibitor, AZD1480. In vitro, α-SYN exposure activated the JAK/STAT pathway in microglia and macrophages, and treatment with AZD1480 inhibited α-SYN-induced major histocompatibility complex Class II and inflammatory gene expression in microglia and macrophages by reducing STAT1 and STAT3 activation. For in vivo studies, we used a rat model of PD induced by viral overexpression of α-SYN. AZD1480 treatment inhibited α-SYN-induced neuroinflammation by suppressing microglial activation, macrophage and CD4
+ T-cell infiltration and production of proinflammatory cytokines/chemokines. Numerous genes involved in cell- cell signaling, nervous system development and function, inflammatory diseases/processes, and neurological diseases are enhanced in the substantia nigra of rats with α-SYN overexpression, and inhibited upon treatment with AZD1480. Importantly, inhibition of the JAK/STAT pathway prevented the degeneration of dopaminergic neurons in vivo. These results indicate that inhibiting the JAK/STAT pathway can prevent neuroinflammation and neurodegeneration by suppressing activation of innate and adaptive immune responses to α-SYN. Furthermore, this suggests the feasibility of targeting the JAK/STAT pathway as a neuroprotective therapy for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]- Published
- 2016
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