title: Inhibition of the JAK/STAT Pathway Protects Against α-Synuclein-Induced Neuroinflammation and Dopaminergic 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.
  
  
  
  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.affiliation: Departments of Cell, Developmental and Integrative Biology, hqin@uab.edu tika@uab.edu.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
authors.affiliation: Departments of Cell, Developmental and Integrative Biology.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Buckley
authors.affiliation: Neurology, and.
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Cell, Developmental and Integrative Biology.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Cell, Developmental and Integrative Biology.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fox
authors.affiliation: Departments of Cell, Developmental and Integrative Biology.
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Meares
authors.affiliation: Departments of Cell, Developmental and Integrative Biology.
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Departments of Cell, Developmental and Integrative Biology.
authors.forename: Zhaoqi
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Neurology, and.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Harms
authors.affiliation: Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Neurology, and.
authors.forename: David G
authors.identifier: 0000-0003-2921-8348
authors.initials: DG
authors.lastname: Standaert
authors.affiliation: Departments of Cell, Developmental and Integrative Biology, hqin@uab.edu tika@uab.edu.
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects*; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors*; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000633:toxicity*
chemical_list: C545606:AZD 1480; D018696:Neuroprotective Agents; D011720:Pyrazoles; D011743:Pyrimidines; D050791:STAT Transcription Factors; D051844:alpha-Synuclein; D053612:Janus Kinases
keywords: JAK/STAT pathway; JAKinibs; Parkinson's disease; neurodegeneration; neuroinflammation; α-synuclein