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Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily driven by the degeneration of dopaminergic neurons, with limited therapeutic interventions currently available. Among the critical factors in PD pathogenesis, DJ-1, a multifunctional protein, has emerged as a key neuroprotective agent against oxidative stress—a major contributor to the disease. Recent research has emphasized the pivotal role of DJ-1 dimerization in enhancing its neuroprotective capabilities. This review provides an in-depth analysis of the molecular mechanisms underlying DJ-1 dimerization and its relevance to PD. Specifically, we specifically explore how dimerization stabilizes DJ-1, enhances its antioxidative properties, improves mitochondrial function, and modulates key cellular pathways essential for neuronal survival. Furthermore, we discuss the molecular determinants governing DJ-1 dimerization, highlighting its potential both as a biomarker for PD diagnosis and a promising therapeutic target. By synthesizing current advancements, we propose that targeting DJ-1 dimerization may offer innovative strategies to slow PD progression and bolster neuronal health. This review positions DJ-1 as a central focus in PD research, paving the way for future studies aimed at developing neuroprotective therapies. Neuroprotective Role of DJ-1 Dimers and Their Regulation in PD. This schematic highlights the neuroprotective role of DJ-1 dimers in PD. Post-translational modifications (PTMs) such as oxidation (O), phosphorylation (P), and S-nitrosylation (S), as well as molecular chaperones like BAG1, regulate the formation of DJ-1 dimers. DJ-1 dimerization is emphasized as a critical feature for stabilizing its structure and enhancing its neuroprotective functions, including antioxidative stress regulation (mitigating reactive oxygen species ROS), mitochondrial homeostasis, molecular chaperone activity, and neuronal survival. Therefore, screening for factors that regulate DJ-1 dimer formation may represent a novel therapeutic target for protecting neurons.
Lv et al. (Mon,) studied this question.