DJ-1 Protein Ameliorates Mitochondrial Dynamics Imbalance via the PGC1α/DRP1 Pathway in Parkinson's Disease

Background: Parkinson's disease (PD) is characterized by progressive neuron loss. Current therapies, like levodopa offer symptomatic relief but do not halt disease progression. , highlighting the need for neuroprotective strategies. Objective: This study aimed to evaluate the neuroprotective effects of recombinant DJ-1 protein in a PD cell model and to elucidate its mechanism related to mitochondrial dynamics. Methods: An in vitro PD model was established by treating SH-SY5Y cells with 6-hydroxydopamine (6-OHDA). Cells were then treated with recombinant DJ-1 protein. Assessments included cell viability (CCK-8), (flow cytometry), mitochondrial morphology (confocal microscopy), reactive oxygen species (ROS) levels, membrane potential (MMP), DJ-1 expression/localization (qRT-PCR/immunofluorescence), and key pathway protein levels (western blot for proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and dynamin-related protein 1 (DRP1)). Bioinformatic analysis predicted DJ-1 targets. Results: 6-OHDA induced significant apoptosis and mitochondrial dysfunction, including fragmentation, elevated ROS, and reduced MMP. Recombinant DJ-1 protein treatment enhanced viability, suppressed apoptosis, and restored mitochondrial morphology and function. Mechanistically, DJ-1 activated the PGC1α/DRP1 pathway, attenuating excessive fission and oxidative stress to maintain mitochondrial homeostasis. Conclusion: Recombinant DJ-1 protein exert neuroprotective effects in a PD cell model by ameliorating mitochondrial dysfunction via the PGC1α/DRP1 pathway, representing a potential novel therapeutic approach for PD.