Oleanolic acid activates the JNK-Sp1-DJ-1 axis to promote mitophagy-mediated neuroprotection in dopaminergic neurons for Parkinson's disease treatment.

Abstract

Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by mitochondrial dysfunction and oxidative stress. Although levodopa remains the gold standard for managing PD motor symptoms, it lacks neuroprotective and disease-modifying effects, highlighting the need for new neuroprotective therapies. Mitophagy, the selective mitochondrial degradation by autophagy, is critical for neuronal health. Oleanolic acid, a natural hepatoprotective compound, shows uncertain efficacy in PD treatment. This study investigated the neuroprotective effects and underlying mechanisms of oleanolic acid using the 1-methyl-4-phenylpyridinium (MPP⁺)-induced cellular model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. In vitro, oleanolic acid demonstrated dopaminergic neuroprotection by reducing mitochondrial dysfunction and reactive oxygen species accumulation in PD cells. It upregulated the mitophagic protein DJ-1, enhancing the sequestration of damaged mitochondria into autophagosomes by mitophagy. DJ-1 knockdown attenuated oleanolic acid's neuroprotection, confirming DJ-1's role in oleanolic acid's action. In vivo, pre-treatment with oleanolic acid in MPTP-induced PD mice prevented PD-like motor symptoms, reduced neuronal death in the substantia nigra, and mitigated striatal neurodegeneration. Post-treatment with oleanolic acid not only reduced these effects but also increased Bcl-2 and DJ-1 levels in the substantia nigra and striatum. In vitro, oleanolic acid activated JNK for Sp1 upregulation and nuclear translocation, which induced DJ-1 expression. Computational modeling predicted that oleanolic acid likely interacts with JNK, suggesting this binding might be necessary for JNK-Sp1-DJ-1 axis activation for mitophagy-driven neuroprotection. These results highlight oleanolic acid's potential as a therapeutic agent in PD prevention and treatment via the JNK-Sp1-DJ-1 pathway. Further studies are required to validate its efficacy.