Infection and herbicide exposure implicate c-Abl kinase in α-Synuclein Ser129 phosphorylation

BackgroundParkinsons disease is a complex multifactorial neurodegenerative disorder characterized by -Synuclein aggregation in Lewy bodies, with phosphorylation at serine 129 (pSer129) being a critical pathological hallmark. However, the exact mechanisms by which environmental triggers lead to this disease phenotype remain poorly understood. In this study we compare the effects of an exemplary infection and a certain pesticide exposure on the generation of pSer129 -Synuclein, with a focus on the involvement of cellular kinases in this process. MethodsTwo distinct environmental stressors were applied to neuronal cells: the pesticide rotenone and the well-studied gastric bacterium Helicobacter pylori (H. pylori). Phosphorylation of Ser129 -Synuclein was assessed by immunofluorescent staining and Western blotting. Cells were treated with mechanistically distinct c-Abl inhibitors, and pSer129 -Synuclein was detected using Western blotting and activities of the upstream serine-threonine kinase were predicted by kinase profiling and Western blotting, analyzed by one-way ANOVA followed by Tukeys multiple comparisons test. Moreover, transcriptome analyses of treated cells were performed and ingenuity pathway analysis and Deseq2 were applied to unravel the affected neurodegenerative pathways. ResultsThe functional analysis of our RNA sequence data demonstrated that both H. pylori and rotenone induced oxidative stress and neuroinflammation by stimulating neurodegenerative pathways. Rotenone and H. pylori activated c-Abl, likely through the induced oxidative stress and promoted -Synuclein phosphorylation. The kinase inhibitors Ponatinib and Asciminib effectively prevented pSer129 -Synuclein accumulation and reversed associated gene expression changes induced by rotenone or H. pylori. Moreover, GSK3{beta} appeared to be involved in the induction of Ser129 phosphorylation via activated c-Abl. Furthermore, H. pyloris vacuolating cytotoxin appeared to play a crucial role in the phosphorylation of pSer129 -Synuclein by c-Abl. ConclusionsThese findings highlight the pivotal role of c-Abl in -Synucleopathies and provide insights into shared mechanisms between infection and pesticide exposure, offering potential therapeutic targets for Parkinsons disease and related pathologies involving -Synuclein modification.