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.
Highlights
Parkinson’s disease is the second most common neurodegenerative disease, affecting ~1% of the population older than 50, and 2–3% of the population older than 65 years of age [1]
The major findings of this paper are the observation that Withaferin A (WA) protects against Parkinson’s disease (PD)
Our findings show that WA treatment leads to a restoration of the genes associated with dopamine synthesis and transport, and a relief of the genes related to neuroinflammation in substantia nigra pars compacta (SNc), which may contribute to the neuroprotective effects of WA against PD
Summary
Parkinson’s disease is the second most common neurodegenerative disease, affecting ~1% of the population older than 50, and 2–3% of the population older than 65 years of age [1]. To investigate the potential mechanisms underlying the neuroprotective role of WA, we performed genome-wide sequencing analysis to inspect the differential expression genes (DEGs) in SNc of WA-treated PD mouse models. The damaged mitochondria release mitochondrial DNA (mtDNA) in SNc of both PD patients and MPTP-received mice, causing STING-mediated neuroinflammation, which deteriorate PD progression [24, 27, 28]. STING can be activated by DAMPs and PAMPs, and causes the loss of SNc dopaminergic neurons, which may be an undiscovered mechanism underlying PD pathogenesis. To obtain a comprehensive understanding of the neuroprotective effects of WA, we employed the multiple PD models to better model the degenerative features of PD, including the MPTPinduced PD mouse model, the AAV-mediated human α-syn overexpression PD model and the MPP+ treated human dopaminergic neurons. Our work identifies WA as an important anti-PD agent and proposes a pathway that can be targeted for treatment of PD and related neurodegenerative disorders
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