Analysis of multidimensional molecular mechanisms in Parkinson's disease and precise therapeutic strategies.
TL;DR
Current mechanistic insights inspire targeted therapeutic strategies comprising α-synuclein inhibitors, mitochondrial protectants, anti-inflammatory agents, and novel cell death pathway blockers, alongside gut-brain axis interventions for PD, but these approaches face substantial challenges.
Abstract
Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, is characterized by progressive loss of dopaminergic neurons in the substantia nigra and striatal dopamine deficiency, leading to motor dysfunction. The complex pathogenesis involves impaired protein homeostasis with α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation, including NLRP3 inflammasome activation. Newly identified regulated cell death pathways - including ferroptosis, cuproptosis, pyroptosis, and necroptosis - have further expanded current understanding of PD pathology, while gut-brain axis interactions may contribute to peripheral-central communication and disease progression. These mechanistic insights inspire targeted therapeutic strategies comprising α-synuclein inhibitors, mitochondrial protectants, anti-inflammatory agents, and novel cell death pathway blockers, alongside gut-brain axis interventions. However, these approaches face substantial challenges including limited blood-brain barrier penetration, insufficient target specificity, and individual genetic heterogeneity. Future research should prioritize developing multi-target combination therapies, integrating multi-omics and computational approaches for biomarker identification and patient stratification, while advancing clinical translation of gene- and cell-based therapies. Through interdisciplinary collaboration and precision medicine implementation, disease-modifying treatments for PD may become increasingly feasible.