Abstract
BackgroundThe R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson’s disease (PD). Peripheral inflammation and gut microbiota are closely associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD. Porphyromonas gingivalis (Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD.MethodsIn this study, live Pg were orally administrated to animals, three times a week for 1 month. Pg-derived lipopolysaccharide (LPS) was used to stimulate mononuclear cells in vitro. The effects of oral Pg administration on the gut and brain were evaluated through behaviors, morphology, and cytokine expression.ResultsDopaminergic neurons in the substantia nigra were reduced, and activated microglial cells were increased in R1441G mice given oral Pg. In addition, an increase in mRNA expression of tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) as well as protein level of α-synuclein together with a decrease in zonula occludens-1 (Zo-1) was detected in the colon in Pg-treated R1441G mice. Furthermore, serum interleukin-17A (IL-17A) and brain IL-17 receptor A (IL-17RA) were increased in Pg-treated R1441G mice.ConclusionsThese findings suggest that oral Pg-induced inflammation may play an important role in the pathophysiology of LRRK2-associated PD.
Highlights
The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson’s disease (PD)
Oral Porphyromonas gingivalis (Pg) induced dopaminergic neuronal degeneration in the substantia nigra pars compacta (SNpc) of mutant LRRK2 mice To examine whether oral Pg can induce dopaminergic neuronal degeneration, Pg was administrated orally to FVBN mice and LRRK2 R1441G transgenic mice for a month
Immunoblot further confirmed that protein level of cleaved active caspase-3 was greatly increased in the SN of LRRK2 R1441G mice after Pg treatment compared to FVBN mice (Fig. 1c)
Summary
The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson’s disease (PD). Peripheral inflammation and gut microbiota are closely associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD. Porphyromonas gingivalis (Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD. Leucine-rich repeat kinase 2 (LRRK2) mutants are the most common genetic factors in the pathogenesis of PD [4]. Activation of LRRK2 protects against infection in the gut, but causes neurodegeneration in the brain [9, 10]
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