The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease

Lashgari, Naser Aldin; Roudsari, Nazanin Momeni; Momtaz, Saeideh; Sathyapalan, Thozhukat; Abdolghaffari, Amir Hossein; Sahebkar, Amirhossein

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder in which inflammation and oxidative stress play key etiopathological role. The pathology of PD brain is characterized by inclusions of aggregated α-synuclein (α-SYN) in the cytoplasmic region of neurons. Clinical evidence suggests that stimulation of pro-inflammatory cytokines leads to neuroinflammation in the affected brain regions. Upon neuroinflammation, the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway, and other transcription factors such as nuclear factor κB (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), mammalian target of rapamycin (mTOR), and toll-like receptors (TLRs) are upregulated and induce the microglial activation, contributing to PD via dopaminergic neuron autophagy. Aberrant activation or phosphorylation of the components of JAK/STAT signaling pathway has been implicated in increased transcription of the inflammation-associated genes and many neurodegenerative disorders such as PD. Interferon gamma (IFN-γ), and interleukine (IL)-6 are two of the most potent activators of the JAK/STAT pathway, and it was shown to be elevated in PD. Stimulation of microglial cell with aggregated α-SYN results in production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and IL-1β in PD. Dysregulation of the JAK/STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach. So far, a variety of synthetic or natural small-molecule JAK inhibitors (Jakinibs) have been found promising in managing a spectrum of ailments, many of which are in preclinical research or clinical trials. Herein, we provided a perspective on the function of the JAK/STAT signaling pathway in PD progression and gathered data that describe the rationale evidence on the potential application of Jakinibs to improve neuroinflammation in PD.

Citation

Lashgari, N. A., Roudsari, N. M., Momtaz, S., Sathyapalan, T., Abdolghaffari, A. H., & Sahebkar, A. (2021). The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease. Journal of Neuroimmunology, 361, Article 577758. https://doi.org/10.1016/j.jneuroim.2021.577758

• Journal Article Type: Review
• Acceptance Date: Oct 25, 2021
• Online Publication Date: Oct 27, 2021
• Publication Date: Dec 15, 2021
• Deposit Date: Dec 26, 2021
• Publicly Available Date: Oct 28, 2022
• Journal: Journal of Neuroimmunology
• Print ISSN: 0165-5728
• Electronic ISSN: 1872-8421
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 361
• Article Number: 577758
• DOI: https://doi.org/10.1016/j.jneuroim.2021.577758
• Keywords: Parkinson's disease; Neuroinflammation; JAK/STAT; Jakinibs
• Public URL: https://hull-repository.worktribe.com/output/3868382