Environmental Factors Influence α‐synuclein Transport In The Gut‐brain Axis In A Rodent Model Of Parkinsonism

In recent years, idiopathic Parkinson's disease (PD) has been hypothesized to be triggered by the gastrointestinal (GI)‐mediated transport of environmental pathogens; these pathogens then travel retrogradely to the central nervous system in a bottom‐up fashion via the vagus nerve, and induce the typical degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc). The presence of misfolded α‐synuclein in SNpc is the characteristic histological hallmark of PD. We have shown previously that oral co‐administration of subthreshold doses of paraquat (1mg/kg) and lectins (0.05%w/v) causes GI dysmotility and may be implicated in PD's etiology. In the present work we aimed to further characterize the effects of this model of Parkinsonism on the gut‐brain axis. Rat groups were gavaged with i) 1% sucrose (control); or ii) 0.5% lectins + paraquat, 1 mg/kg (200μl for 7 days). Motor behavior, and gastric motility/tone were measured 14 and 30 days post‐gavage, via strain gauges sewn to the anterior gastric surface. At the end of the experiment the GI tract and the brainstem were extracted and processed for immunohistochemistry. Organotypic cultures of stomach and small intestine of naïve rats were incubated up to three days in a culture medium containing 0.5% lectins prior to immunohistochemistry. Motor behavioral tests (vibrissae and stepping tests) revealed initial small, albeit significant, motor dysfunctions in the tested rats at 2 weeks post treatment (N=10), the motor dysfunctions were more pronounced at 4 weeks post treatment (N=10). Levodopa (4 mg/kg b.i.d.) re‐established normal motor behavior (N=12). Organotypic cultures revealed that lectins were present in NOS‐ and in NeuN‐ immunoreactive myenteric neurons, as well as in nerve fibers, likely of extrinsic vagal origin. As reported previously (DDW 2017), this experimental model is associated with gastric motor impairment. Tissues from the stomach, small and large intestine of these rats revealed the presence of misfolded α‐synuclein in 40–60 % of myenteric neurons. The presence of α‐synuclein was noted in neurons of the dorsal motor nucleus of the vagus and the SNpc at two weeks post treatment. At four weeks post treatment, the expression of α‐synuclein was more pronounced, and was accompanied by a significant loss of tyrosine‐hydroxylase immunoreactive neurons of the SNpc. The data suggest that prolonged oral exposure to subthreshold doses lectins and paraquat induces a Parkinsonian phenotype that mimics the prodromal GI dysfunctions and α‐synucleopathy progression in the gut‐brain axis observed in patients. Support or Funding Information NIH DK 55530 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .