Gene–Environment Interplay in Converging Pathways to α-Synuclein Ser129 Phosphorylation H. pylori, Rotenone, and ATG16L1 Polymorphism in Parkinson’s Disease

This study investigated how environmental triggers (H. pylori infection and rotenone exposure) induce phosphorylation of α-synuclein at Ser129—a hallmark of Parkinson's disease—and explored the interplay with genetic susceptibility via the autophagy-related ATG16L1 rs2241880 polymorphism. In SH-SY5Y, both H. pylori infection and rotenone exposure activated the tyrosine kinase c-Abl and serine-threonine kinase GSK3β, resulting in accumulation of α-synuclein phosphorylated at Ser129. Pharmacological inhibition of these kinases (using c-Abl inhibitors [Ponatinib, Asciminib] and GSK3β inhibitors) significantly attenuated phosphorylation of α-synuclein at Ser129. The virulence factor VacA of H. pylori was critical for this effect, whereas in HeLa cells the ATG16L1 rs2241880 G allele exacerbated autophagy deficits and phosphorylation at Ser129 of α-synuclein during infection, highlighting a gene-environment interaction. Key limitations included the use of non-dopaminergic cell models and acute exposure paradigms, which may not fully replicate chronic Parkinson's disease progression. Future research should validate findings in induced pluripotent stem cell-derived neurons or in vivo models, explore effects of chronic toxin exposure, and investigate therapeutic targeting of c-Abl/GSK3β in genetically susceptible populations. This work establishes c-Abl/GSK3β as convergent mediators of environmental Parkinson's disease triggers and positions ATG16L1 as a genetic modifier of pathogen-driven neurodegeneration, offering novel insights into Parkinson's disease pathogenesis and personalized treatment strategies.