Emerging molecular mechanism of neuroinflammation in Parkinson's disease: A JAK/STAT and TGFβ/SMAD signaling crosstalk.

Authors

Kaustav Purkayastha, Abhideep Roy, Pallab Bhattacharya, Anupom Borah

Published in

Biochimica et biophysica acta. General subjects. Pages 130989. Aug 18, 2026. Epub Aug 18, 2026.

Abstract

Neuroinflammation has emerged as a convergent pathological signature of Parkinson's disease (PD), shaping both its onset and progression. Persistent activation of glial cells, driven by elevated proinflammatory cytokines, creates a self-reinforcing inflammatory milieu that accelerates dopaminergic neurodegeneration. Microglia, astrocytes, and Toll-like receptor (TLR)-mediated pathways converge to amplify this response, linking innate immune activation to chronic neurotoxicity. At the transcriptional level, the JAK/STAT signaling cascade governs cytokine-driven inflammation by promoting the expression of proinflammatory mediators, thereby sustaining immune activation. In contrast, the TGF-β/SMAD signaling functions as a critical counter-regulatory mechanism, maintaining immune quiescence and neural homeostasis through canonical SMAD-dependent signaling. However, in PD, this anti-inflammatory pathway becomes impaired, diminishing its neuroprotective influence. Emerging evidence suggests that hyperactivated JAK/STAT signaling can suppress TGF-β/SMAD activity, establishing a pathological dominance of proinflammatory signaling over neuroprotective restraint. This review synthesizes current understanding of the mechanistic interplay between these critical pathways, proposing that the imbalance between JAK/STAT activation and TGF-β/SMAD suppression represents a key candidate regulatory interface governing the neuroinflammatory trajectory of PD. Unraveling this crosstalk provides new insight into how signaling hierarchies shape glial phenotypes and neurodegeneration, while highlighting potential therapeutic strategies aimed at restoring immune equilibrium to mitigate PD progression.

PMID:
42612757
Bibliographic data and abstract were imported from PubMed on 19 Aug 2026.

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