Infection and herbicide exposure implicate c-Abl kinase in a-synuclein serine 129 phosphorylation

Parkinson's disease is a complex multifactorial neurodegenerative disorder characterized by a-synuclein aggregation in Lewy bodies, with phosphorylation at serine 129 (pSer129) being a critical pathological hallmark. However, the exact mechanisms linking the diverse triggers to a unified disease phenotype remain poorly understood. In this study we aim to investigate the common effects of infection and pesticide exposure on accumulation of pSer129 a-synuclein, focusing on the involvement of c-Abl in this process. The functional analysis of RNA sequencing results demonstrated that both H. pylori and rotenone induce oxidative stress, neuroinflammation and neurodegenerative pathways. Rotenone and H. pylori activated c-Abl, perhaps through the induced oxidative stress and promote a-synuclein phosphorylation. The kinase inhibitors ponatinib, nilotinib, and asciminib effectively rescued pSer129 a-synuclein and reversed associated gene expression changes induced by rotenone or H. pylori. Moreover, GSK3ß is involved in the induction of pSer129 by c-Abl. Furthermore, H. pylori's vacuolating cytotoxin play a crucial role in phosphorylation of pSer129 a-synuclein through c-Abl. Overall design: SH-SY5Y cells (ATCC, CRL-2266, RRID: CVCL_0019) were infected with Helicobacter pylori WT P12 strain (Hpy) or treated with 10µM of Rotenone in the presence or absence of 50nM of the ABL1 inhibitor Ponatinib. 6 hours after treatment, transcriptional responses were studied by RNAseq. Vehicle only (DMSO) controls were also included.