Splanchnic-spinal transmission of gut-initiated α-synucleinopathy

Abstract

Gut-initiated -synucleinopathy is proposed to spread from the gastrointestinal tract to the CNS, contributing to Parkinson's disease (PD), but whether routes beyond the vagus nerve are involved remains unclear. Using complementary intracolonic rotenone and gastroduodenal -synuclein PFF models, we combined pathway-specific surgical interruption with longitudinal behavioral analysis and anatomical mapping of pathological -synuclein. In the intracolonic rotenone model, interruption of the prevertebral ganglia/splanchnic-spinal axis more strongly attenuated behavioral deficits and -synuclein pathology than vagotomy. In the gastroduodenal PFF model, both vagal and splanchnic-spinal pathways contributed to pathology propagation. Early after PFF inoculation, pathological -synuclein was detected in peripheral neural structures associated with both routes. Consistent with these findings, spinal pathology was evident in human PD. Together, these results identify the splanchnic-spinal pathway as a key component of body-first Parkinson's disease, broadening current models of peripheral-to-central disease progression and informing efforts to target early peripheral disease progression.