流行病学和组织病理学的研究结果显示，不正确折叠的α-突触核蛋白蛋白质可能从肠道传播到脑部，并增加帕金森病（PD）的风险。虽然过去的实验研究依赖于对小鼠模型进行肠道注射外源性重组α-突触核蛋白纤维，以研究肠道到脑部的α-突触核蛋白转移，但肠道内不正确折叠的α-突触核蛋白的可能起源还不明确。我们最近证明了肠粘膜感觉细胞中存在α-突触核蛋白的表达。在这项研究中，我们使用表达人类α-突触核蛋白的小鼠肠道类器官培养体，观察肠道上皮细胞中的α-突触核蛋白与缺乏α-突触核蛋白表达的迷走球状神经元共培养后的转移情况。在表达病理性人类α-突触核蛋白但不表达小鼠α-突触核蛋白的完整小鼠中，α-突触核蛋白种子纤维聚集活性在肠道、迷走神经和背侧运动核组织的α-突触核蛋白种子纤维聚集检测中显现。在新近经过基因改造的小鼠模型中，将病理性人类α-突触核蛋白的表达限制在肠道上皮细胞中，α-突触核蛋白种子纤维聚集活性可以传递到迷走神经和背侧运动核。在诱导肠道上皮细胞中α-突触核蛋白的表达之前进行剖腹迷走神经切断术可以有效保护脑干不受α-突触核蛋白种子纤维聚集活性的影响。总体而言，这些发现突出了可能存在于肠道粘膜细胞中的纤维状α-突触核蛋白的一种新的潜在非神经元源。

Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.