ISGylation of STING contributes to neuroinflammation and neurodegeneration via activating c-Fos in Parkinson's disease models

Type-I interferons (IFNs), as key mediators of innate immune response, have been implicated in neurodegenerative diseases, including Parkinson’s disease (PD). IFN exerts various biological effects by activating hundreds of interferon-stimulated genes (ISGs), including ISG15. ISG15 mediate ISGylation by covalently linking modifying target proteins including STING. The present study aims to explore whether the IFN-ISG15 pathway contributes to PD pathogenesis by ISGylating its target STING. This study showed that ISG15 and ISGylation of STING (ISG-STING) were induced in in vitro PD models, including MPP ⁺ -treated and lentiviral synucleinA53T-infected SH-SY5Y cells. Transcriptomic analyses showed that c-Fos, an immediate early gene (IEG), is prominently induced by overexpression of STING. Overexpression of STING-WT promoted ISGylation of STING, increased c-Fos and cell death in MPP ⁺ treated SH-SY5Y, while non-ISGylation mutation STING K289A and shISG15 reduced the ISG-STING, c-Fos, and cell death. In in vivo PD models, including MPTP-injected and AAV-synucleinA53T mice, STING-K289A and shISG15 reduced the ISG15, ISG-STING, c-Fos, neuroinflammation, and dopaminergic neuronal death, and restored compromised behaviors. The present study supported that ISGylation of STING augmented its function and activity (gain-of-function), promoted PD pathogenesis by activating c-Fos and driving neuroinflammation. ISG-STING augments the induction of downstream IFN and ISG15, which further ISGylates STING, creating a positive feedback loop and potentiating the progression of neurodegenerative disease. Targeting ISG15-mediated ISGylation or ISG15-interacting proteins may provide a novel therapeutic approach for PD.