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Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration.
J Neurosci. 2016 05 04; 36(18):5144-59.JN

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.

SIGNIFICANCE STATEMENT

α-SYN plays a central role in the pathophysiology of PD through initiation of neuroinflammatory responses. Using an α-SYN overexpression PD model, we demonstrate a beneficial therapeutic effect of AZD1480, a specific inhibitor of JAK1/2, in suppressing neuroinflammation and neurodegeneration. Our findings document that inhibition of the JAK/STAT pathway influences both innate and adaptive immune responses by suppressing α-SYN-induced microglia and macrophage activation and CD4(+) T-cell recruitment into the CNS, ultimately suppressing neurodegeneration. These findings are the first documentation that suppression of the JAK/STAT pathway disrupts the circuitry of neuroinflammation and neurodegeneration, thus attenuating PD pathogenesis. JAK inhibitors may be a viable therapeutic option for the treatment of PD patients.

Authors+Show Affiliations

Departments of Cell, Developmental and Integrative Biology, hqin@uab.edu tika@uab.edu.Departments of Cell, Developmental and Integrative Biology.Neurology, and.Departments of Cell, Developmental and Integrative Biology.Departments of Cell, Developmental and Integrative Biology.Departments of Cell, Developmental and Integrative Biology.Departments of Cell, Developmental and Integrative Biology.Departments of Cell, Developmental and Integrative Biology.Neurology, and.Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.Neurology, and.Departments of Cell, Developmental and Integrative Biology, hqin@uab.edu tika@uab.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27147665

Citation

Qin, Hongwei, et al. "Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 36, no. 18, 2016, pp. 5144-59.
Qin H, Buckley JA, Li X, et al. Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration. J Neurosci. 2016;36(18):5144-59.
Qin, H., Buckley, J. A., Li, X., Liu, Y., Fox, T. H., Meares, G. P., Yu, H., Yan, Z., Harms, A. S., Li, Y., Standaert, D. G., & Benveniste, E. N. (2016). Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 36(18), 5144-59. https://doi.org/10.1523/JNEUROSCI.4658-15.2016
Qin H, et al. Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration. J Neurosci. 2016 05 4;36(18):5144-59. PubMed PMID: 27147665.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic Neurodegeneration. AU - Qin,Hongwei, AU - Buckley,Jessica A, AU - Li,Xinru, AU - Liu,Yudong, AU - Fox,Thomas H,3rd AU - Meares,Gordon P, AU - Yu,Hao, AU - Yan,Zhaoqi, AU - Harms,Ashley S, AU - Li,Yufeng, AU - Standaert,David G, AU - Benveniste,Etty N, PY - 2015/12/30/received PY - 2016/03/22/accepted PY - 2016/5/6/entrez PY - 2016/5/6/pubmed PY - 2017/8/15/medline KW - JAK/STAT pathway KW - JAKinibs KW - Parkinson's disease KW - neurodegeneration KW - neuroinflammation KW - α-synuclein SP - 5144 EP - 59 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 36 IS - 18 N2 - UNLABELLED: 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. SIGNIFICANCE STATEMENT: α-SYN plays a central role in the pathophysiology of PD through initiation of neuroinflammatory responses. Using an α-SYN overexpression PD model, we demonstrate a beneficial therapeutic effect of AZD1480, a specific inhibitor of JAK1/2, in suppressing neuroinflammation and neurodegeneration. Our findings document that inhibition of the JAK/STAT pathway influences both innate and adaptive immune responses by suppressing α-SYN-induced microglia and macrophage activation and CD4(+) T-cell recruitment into the CNS, ultimately suppressing neurodegeneration. These findings are the first documentation that suppression of the JAK/STAT pathway disrupts the circuitry of neuroinflammation and neurodegeneration, thus attenuating PD pathogenesis. JAK inhibitors may be a viable therapeutic option for the treatment of PD patients. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/27147665/Inhibition_of_the_JAK/STAT_Pathway_Protects_Against_α_Synuclein_Induced_Neuroinflammation_and_Dopaminergic_Neurodegeneration_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=27147665 DB - PRIME DP - Unbound Medicine ER -