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This study demonstrates that alpha-synuclein pathology, a hallmark of Parkinson's disease, can spread from the gut to the central nervous system through the splanchnic-spinal pathway in addition to the previously recognized vagus nerve route. Using rodent models with intracolonic rotenone and gastroduodenal alpha-synuclein preformed fibrils, researchers found that interrupting the splanchnic-spinal pathway more effectively reduced Parkinson's-related behavioral deficits and pathology than vagotomy alone. The findings were supported by detection of spinal pathology in human Parkinson's disease patients, suggesting multiple peripheral routes contribute to disease progression.
Why it matters
These findings expand our understanding of how Parkinson's disease may originate in the gut and spread to the brain, revealing that the splanchnic-spinal pathway plays a significant role alongside vagal transmission. This knowledge could inform new therapeutic strategies targeting early peripheral disease progression through multiple pathways rather than focusing solely on vagus nerve intervention.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: Splanchnic-spinal transmission of gut-initiated α-synucleinopathy