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Figure 3. Molecular mechanisms of periodontal pathogen-driven neurodegeneration relevant to PD. (A) Gingipain-mediated α-syn pathology in neuronal soma. Virulence factors from Porphyromonas gingivalis, particularly Kgp and Rgp, may cleave native α-syn into truncated fragments that undergo phosphorylation, such as pSer129, and rapidly self-assemble into Lewy body-like aggregates. Concurrent mitochondrial dysfunction and ROS generation may further amplify protein aggregation and neuronal injury; (B) Microglial NLRP3 inflammasome activation. Periodontal-derived inflammatory signals, including LPS, may engage TLR4 on microglia, activate NF-κB, and prime NLRP3 inflammasome components. ROS accumulation and ionic fluxes, such as K+ efflux, may promote assembly of the inflammasome complex (NLRP3, ASC, and pro-caspase-1), leading to caspase-1 activation and maturation of IL-1β, thereby intensifying neuroinflammation. This response may be further amplified by IFN-γ signaling and downstream cytokines such as TNF-α; (C) Metabolic vulnerability linking oxidative stress to ferroptosis. Reduced G6PD activity may limit NADPH/GSH-dependent antioxidant capacity, thereby facilitating ferrous iron-driven lipid peroxidation and ferroptotic cell death. This pathway highlights a potential convergence of redox imbalance, iron dysregulation, and periodontal inflammation-associated neurodegenerative susceptibility. PD: Parkinson’s disease; α-syn: α-synuclein; pSer129: phospho-Ser129; Kgp: lysine-gingipain; Rgp: arginine-gingipain; ROS: reactive oxygen species; LPS: lipopolysaccharide; TLR4: Toll-like receptor 4; NF-κB: nuclear factor kappa B; NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3; ASC: apoptosis-associated speck-like protein containing a CARD; IL-1β: interleukin-1β; IFN-γ: interferon-γ; TNF-α: tumor necrosis factor-α; G6PD: glucose-6-phosphate dehydrogenase; NADPH: nicotinamide adenine dinucleotide phosphate; GSH: glutathione.