HSF1 Activator Azadiradione Ameliorates Parkinson’s Disease and Extends Lifespan in Preclinical Models: Analysis of Underlying Molecular Mechanism

Parkinson’s disease (PD) affects millions worldwide, with no efficient therapy currently available. A major cause of the initiation and progression of this degenerative disease is the dysfunctional cellular protein quality control system (PQC), leading to the accumulation of toxic protein aggregates in neurons. We previously reported azadiradione (AZD), a small molecule (MW 451 Da), as a potent inducer of heat shock factor 1 (HSF1) activity, which could alleviate cellular toxicity induced by misfolded proteins by upregulating the levels of inducible molecular chaperones and proteasome activity. Here, we show the multifaceted effect of AZD in enhancing the capacity of PQC machinery in cells, fruit flies, and a PD mouse model. AZD activated HSF1 by promoting its phosphorylation at S326 through MEK. In parallel, AZD boosted protein degradation through increased chymotrypsin-like proteasome activity, upregulation of the ubiquitin ligase CHIP. AZD induced autophagy, marked by elevated levels of Beclin 1, ATG7, and ULK1 phosphorylation at S555, along with mTORC1 inhibition via AMPK activation. Surprisingly, the calorie restriction pathway was also upregulated upon AZD treatment, as demonstrated by the enhanced phosphorylation of FOXO3 and FOXO1, along with increased activity of their target enzymes SOD and catalase. Notably, AKT activity was also suppressed in AZD-treated cells. In vivo, AZD improved motor function, dopaminergic neuron survival, and tyrosine hydroxylase activity in an MPTP-induced mouse model of PD, and extended lifespan in Drosophila without compromising fertility or mobility. These findings highlight AZD as a promising therapeutic candidate for restoring PQC and mitigating PD pathology.