Role of Microglial Dysfunction in Parkinson's Disease: From Multifactorial Causes to Neurodegeneration

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons, and its prevalence is increasing, alongside global population aging. Neuroinflammation has been widely recognized as a pivotal contributor to PD pathogenesis, particularly owing to the dual role of microglia in this process. This review systematically identifies the multiple factors regulating microglial function and phenotype, thereby driving PD initiation and progression. Furthermore, aging, a major risk factor for PD, and its profound effects on microglial state and functional dynamics are discussed. Notably, microglial hyperactivation is shown to establish a self-perpetuating cycle of "inflammation-damage-reinflammation" through the excessive release of pro-inflammatory cytokines and chemokines, which exacerbates neuronal degeneration. Lastly, the potential therapeutic strategies targeting microglial dysfunction, including interventions against the senescence-associated secretory phenotype and the modulation of microglial activity, are summarized. By elucidating how multifactorial alterations in microglial states influence PD pathology, this review provides novel insights and directions for advancing therapeutic research in PD.