Acteoside alleviates Parkinson's disease-associated neurodegeneration and oxidative stress via an m6A-dependent Nrf2 regulatory axis.

Parkinson's disease (PD) is a major neurodegenerative disorder. However, current therapeutic strategies do not provide prevention or recovery of neuronal damage. Risk factors, including aging, exogenous toxins, and genetic factors, are strongly related to the development and prognosis of PD. Emerging evidence demonstrates that N6-methyladenosine (m6A) contributes to neurodegeneration in PD. In our study, we found the dysregulation of m6A in PD patients and mouse models, which disrupts the antioxidant mechanism, particularly the expression of Nrf2. In the current study, acteoside (ACT), a compound extracted from Cistanche tubulosa, was found to exert neuroprotective effects in dopaminergic neurons and improved the synucleinopathy in a mouse PD model. ACT significantly improved mitochondria function and alleviated oxidative stress in the PD mice. Moreover, the dysregulated m6A modification was improved by treatment of ACT. ACT treatment was associated with restored METTL3/FTO balance and increased m6A modification of Nrf2 mRNA with elevated Nrf2 mRNA stability and expression. These results provided evidence that ACT could be a potential therapeutic agent for PD.