Cell Communication and Signaling (Mar 2025)
Neuroprotective role and mechanistic insights of DJ-1 dimerization in Parkinson’s disease
Abstract
Abstract 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. Graphical Abstract 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.
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