Drp1 in Parkinson's disease: Mechanisms of disease pathology and the promise of targeted therapeutic strategies.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuron degeneration, mitochondrial dysfunction, and Alpha-synuclein (α-synuclein) aggregation. Dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fission, plays a critical role in PD. Overactivation of Drp1 causes excessive mitochondrial fragmentation, impairing mitochondrial function, increasing Reactive oxygen species (ROS) production, and exacerbating oxidative stress, neuroinflammation, and protein misfolding, all of which contribute to PD pathology. Targeting Drp1 with small molecule inhibitors and gene interventions has shown promise in preclinical models by reducing mitochondrial dysfunction, oxidative damage, and neuronal death. Combination therapies, integrating Drp1 inhibitors with antioxidants and anti-inflammatory agents, have demonstrated synergistic effects. Despite promising preclinical findings, clinical studies on Drp1-targeted therapies are still in early stages, with challenges like specificity and off-target effects. Future research will focus on refining Drp1-targeted therapies, including precision medicine, multi-target strategies, and clinical trials to assess efficacy, safety, and pharmacokinetics. This review highlights Drp1 as a promising therapeutic target for PD and discusses future clinical translation challenges.