Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and pathological α-synuclein aggregation. Growing evidence identifies chronic neuroinflammation—particularly NLRP3 inflammasome activation in microglia—as a central driver for PD onset and progression. Misfolded α-synuclein, mitochondrial dysfunction, and environmental toxins act as endogenous danger signals that prime and activate NLRP3 inflammasome, leading to caspase-1–mediated maturation of IL-1β and IL-18 and subsequent pyroptotic cell death. Impaired mitophagy, due to defects in PINK1/Parkin pathways or receptor-mediated mechanisms, permits accumulation of dysfunctional mitochondria and release DAMPs, thereby amplifying NLRP3 activity. Studies demonstrate that promoting mitophagy or directly inhibiting NLRP3 attenuates neuroinflammation and protects dopaminergic neurons in PD models. Autophagy-inducing compounds, along with NLRP3 inhibitors, demonstrate neuroprotective potential, though their clinical translation remains limited due to poor blood–brain barrier penetration, off-target effects, and insufficient clinical data. Additionally, the context-dependent nature of mitophagy underscores the need for precise therapeutic modulation. This review summarizes current understanding of inflammasome–mitophagy crosstalk in PD, highlights major pharmacological strategies under investigation, and outlines its limitations. Future progress requires development of specific modulators, targeted delivery systems, and robust biomarkers of mitochondrial dynamics and inflammasome activity for slowing PD progression.
Ahmed et al. (Sat,) studied this question.