PGE1 protects against dopaminergic neurodegeneration by suppressing PRL-mediated autophagy via JAK/STAT and PI3K/AKT pathways

MPP⁺-treated MN9D cells and MPTP-induced acute PD mouse models were used. Neuroprotective effects were assessed by cell viability, TUNEL apoptosis assay, behavioral tests, and tyrosine hydroxylase (TH) immunohistochemistry. Transcriptomic sequencing was performed to identify key targets.

PRL was knocked down by siRNA, and pathway involvement was examined using WP1066 (JAK2 inhibitor) and Western blotting. Autophagy was evaluated by LC3-II/I ratio, p62 levels, and transmission electron microscopy. Results: PGE1 attenuated MPP⁺-induced apoptosis and dopaminergic neuronal loss, and alleviated MPTP-induced motor deficits.

Transcriptomic analysis identified PRL as a significantly upregulated target in PD models, which was reversed by PGE1. PRL knockdown enhanced PGE1’s protective effects against TH reduction, α-syn accumulation, and apoptosis. Mechanistically, PGE1 suppressed MPP⁺/MPTP-induced hyperphosphorylation of JAK2, STAT3, PI3K, and AKT.

PRL acted upstream of both pathways, and JAK2/STAT3 functioned upstream of PI3K/AKT. PGE1 also reduced aberrant autophagy, as evidenced by decreased LC3-II/I ratio and p62 levels, and this effect was amplified by PRL knockdown. Conclusions: PGE1 protects against dopaminergic neurodegeneration in PD by inhibiting PRL release, thereby suppressing the JAK2/STAT3 and PI3K/AKT pathways and attenuating excessive autophagy.

These findings identify PRL as a potential therapeutic target and support the repurposing of PGE1 for PD treatment.