Andrographolide upregulates protein quality control mechanisms in cell and mouse through upregulation of mTORC1 function

Abstract

BackgroundHeat shock response (HSR), a component of cellular protein quality control mechanisms, is defective in different neurodegenerative conditions such as Parkinson's disease (PD). Forced upregulation of heat shock factor 1 (HSF1), an HSR master regulator, showed therapeutic promise in PD models. Many of the reported small-molecule HSF1 activators have limited functions. Therefore, identification and understanding the molecular bases of action of new HSF1 activating molecules is necessary. MethodWe used a cell-based reporter system to screen Andrographis paniculata leaf extract to isolate andrographolide as an inducer of HSF1 activity. The andrographolide activity was characterized by analyzing its role in different protein quality control mechanisms. ResultWe find that besides ameliorating the PD in MPTP-treated mice, andrographolide upregulated different machineries controlled by HSF1 and NRF2 in both cell and mouse brain. Andrographolide achieves these functions through mTORC1 activated via p38 MAPK and ERK pathways. NRF2 activation is reflected in the upregulation of proteasome as well as autophagy pathways. We further show that NRF2 activation is mediated through mTORC1 driven phosphorylation of p62/sequestosome 1. Studies with different cell types suggested that andrographolide-mediated induction of ROS level underlies all these activities in agreement with the upregulation of mTORC1 and NRF2-antioxidant pathway in mice. ConclusionAndrographolide through upregulating HSF1 activity ameliorates protein aggregation induced cellular toxicity. General significanceOur results provide a reasonable basis for use of andrographolide in the therapy regimen for the treatment of PD.