The DJ1-Nrf2-STING axis mediates the neuroprotective effects of Withaferin A in Parkinson’s disease

Abstract

The pathogenesis of Parkinson’s disease (PD) remains unclear, and there is no disease-modifying agent for PD. Withaferin A (WA), a naturally occurring compound, has emerged as a neuroprotective agent. However, the mechanisms by which WA is neuroprotective in PD are unknown. Here we show that WA protected against loss of dopaminergic neurons, neuroinflammation, and motor deficits in MPTP-induced PD mouse models. Whole-genome deep sequencing analysis combined with Meta-analysis of human PD studies reveal that DJ1, Nrf2, and STING in substantia nigra pars compacta (SNc) are linked to anti-PD effect of WA. We found that WA activated DJ1 and Nrf2, and suppressed STING within SNc; and overexpression of STING in SNc dampened the effect of WA. Using genetically modified mice (DJ1-KO, Nrf2-KO, STINGgt/gt and STING-KO) and immunolabeling technique, we identified that WA targeted DJ1-Nrf2-STING pathway in dopaminergic neurons; and we demonstrate that STING might be an important factor in PD pathogenesis. In addition, WA alleviated accumulation of phosphorylated α-synuclein (p-α-syn) and insoluble α-syn within SNc in adeno-associated virus (AAV)-mediated human α-syn overexpression PD model. Our comparative analysis on whole-genome transcriptome profiles suggests that STING might be a key target of WA and amantadine in PD treatment. This study highlights a multifaceted role for WA in neuroprotection, and suggests that WA can be a potential candidate for treatment of PD.

Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology

“…Experimental studies have also demonstrated that DJ-1 stimulates Nrf2 translocation to the nucleus end enhances its recruitment to the thioredoxin1 (Trx1) promoter [64]. The DJ-1, Nrf2, and STING (stimulator of interferon genes) pathways are also targeted by the anti-PD naturally occurring compound Withaferin A [65].…”

Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons

“…In this study, incubation with the two drugs indicated a decrease in Nrf2 translocation to the nucleus in agreement with previous results found in different neuronal oxidative cell models [ 24 , 35 ], which could contribute to the GPX decrease observed. The decrease in Nrf2 translocation observed in the combined model of PD and mild to moderate stress could be attributed to a decrease in Nrf2 expression [ 24 , 78 , 79 ], to Nrf2 metabolism alterations [ 80 ], or to a reduction in translocation by itself [ 81 , 82 ], induced by MPP + /MPTP; but it could also be related to the CORT effect mediated by the interaction between GR and Nrf2, owing to GR signalling blockage of Nrf2-mediated cytoprotection from oxidative distress [ 83 ]. In any case, IGF-II co-incubation prevented the Nrf2 nuclear translocation as a direct IGF-II consequence and/or trough interaction with other factors, inhibiting the GR translocation to the nucleus (see below and Figure 7 ).…”

Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop

“…Parp-1, Mmp8, Hmgn1, IL-1, Nfkbid), most of which were significantly upregulated [ 109 •]. Recently, DJ-1 was shown to suppress NFkB signaling by directly interacting with its p65 subunit [ 110 ] and to mitigate inflammation mediated by the STING pathway [ 111 ]. Finally, a link between DJ-1 and regulation of gut microbiome was also described.…”