Oral Exposure to Paraquat Triggers Earlier Expression of Phosphorylated alpha-Synuclein in the Enteric Nervous System of A53T Mutant Human alpha-Synuclein Transgenic Mice

摘要

The misfolded alpha-synuclein protein, phosphorylated at serine 129 (pSer129 alpha-syn), is the hallmark of Parkinson disease (PD). Detected also in the enteric nervous system (ENS), it supports the recent theory that PD could start in the gut, rather than the brain. In a previous study, using a transgenic mouse model of human synucleinopathies expressing the A53T mutant alpha-synuclein (TgM83), in which a neurodegenerative process associated with alpha-synuclein occurs spontaneously in the brain, we have shown earlier onset of pSer129 alpha-syn in the ENS. Here, we used this model to study the impact of paraquat (PQ) a neurotoxic herbicide incriminated in PD in agricultural workers) on the enteric pSer129 alpha-syn expression in young mice. Orally delivered in the drinking water at 10 mg/kg/day for 6-8 weeks, the impact of PQ was measured in a time-dependent manner on weight, locomotor abilities, pSer129 alpha-syn, and glial fibrillary acidic protein (GFAP) expression levels in the ENS. Remarkably, pSer129 alpha-syn was detected in ENS earlier under PQ oral exposure and enteric GFAP expression was also increased. These findings bring additional support to the theory that neurotoxic agents such as PQ initiate idiopathic PD after oral delivery.