Mechanistic of LRRK2-Mediated Pyroptosis Via the NLRP3/Caspase-1/GSDMD Pathway in Parkinson's Disease Progression.

Parkinson’s Disease (PD), the second most common neurodegenerative disorder, is primarily characterized by neuroinflammation and progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta, triggered by the pathological aggregation of α-synuclein (α-syn). Leucine-rich repeat kinase 2 (LRRK2) has been implicated in PD pathogenesis, yet its specific role in disease progression and the underlying mechanisms remain inadequately understood. We constructed the α-syn A53T mutant protein and established a neuroinflammatory model using human HMC3 microglial. A conditioned medium transfer system was developed to study microglia-neuron interactions. Expression of LRRK2, NLRP3, Caspase-1, and gasdermin D (GSDMD), key regulators of pyroptosis, was assessed in microglia. We evaluated DA neuronal apoptosis following α-syn A53T stimulation and validated our findings in Prnp-SNCA A53T transgenic PD mice. Our findings demonstrate that α-syn A53T not only elicits a more pronounced neuroinflammatory response but also enhances LRRK2 kinase activity, while LRRK2 inhibition reduced neuroinflammation. Overexpression of LRRK2 led to a marked upregulation of GSDMD and an exacerbation of the inflammatory response, whereas inhibition of the pyroptotic pathway or NLRP3 knockdown effectively mitigated these pathological changes. Using the conditioned medium system, we confirmed that modulation of the LRRK2/NLRP3/pyroptosis axis profoundly influenced DA neuronal survival. In Prnp-SNCA A53T transgenic mice, both pharmacologic inhibition of LRRK2 and genetic silencing of NLRP3 reduced microglial activation and DA neuronal loss in the central nervous system, significantly improving motor deficits and depressive-like behaviors associated with PD. Collectively, our study suggests that LRRK2 may markedly amplify the pyroptotic response by activating the NLRP3/Caspase-1/GSDMD axis, thereby triggering rapid neuroinflammation and influencing the course of Parkinson’s disease. These findings highlight a pivotal role of LRRK2 in orchestrating pyroptosis-related signaling, providing a plausible mechanistic framework to help explain inter-individual heterogeneity in PD progression. Collectively, our results further underscore the translational potential of targeting LRRK2 as a therapeutic strategy for modulating PD progression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10753-026-02475-w.