Parkinson’s disease (PD) is a neurodegeneration disease with α-synuclein accumulated in the substantia nigra pars compacta (SNpc) and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD. Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy. Although the “gut–brain” hypothesis is proposed to explain the underlying mechanism, where the earlier lesioned site in the brain of gastric α-synuclein and how α-synuclein further spreads are not fully understood. Here we report that caudal raphe nuclei (CRN) are the early lesion site of gastric α-synuclein propagating through the spinal cord, while locus coeruleus (LC) and substantia nigra pars compacta (SNpc) were further affected over a time frame of 7 months. Pathological α-synuclein propagation via CRN leads to neuron loss and disordered neuron activity, accompanied by abnormal motor and non-motor behavior. Potential neuron circuits are observed among CRN, LC, and SNpc, which contribute to the venerability of dopaminergic neurons in SNpc. These results show that CRN is the key region for the gastric α-synuclein spread to the midbrain. Our study provides valuable details for the “gut–brain” hypothesis and proposes a valuable PD model for future research on early PD intervention.

帕金森病（PD）是一种神经退行性疾病，α-突触核蛋白在黑质致密部（SNpc）积聚，当患者被诊断为帕金森病时，SNpc 中大部分多巴胺能神经元丢失。早期探索病理学有助于制定疾病缓解策略。尽管提出“肠-脑”假说来解释其潜在机制，但胃α-突触核蛋白在大脑中的早期病变部位以及α-突触核蛋白如何进一步扩散尚不完全清楚。在这里，我们报告尾中缝核（CRN）是胃α-突触核蛋白通过脊髓传播的早期病变部位，而蓝斑（LC）和黑质致密部（SNpc）在7个月的时间范围内进一步受到影响。通过CRN 的病理性α-突触核蛋白传播会导致神经元丢失和神经元活动紊乱，并伴有异常的运动和非运动行为。在 CRN、LC 和 SNpc 之间观察到潜在的神经元回路，这有助于 SNpc 中多巴胺能神经元的古老。这些结果表明CRN是胃α-突触核蛋白扩散到中脑的关键区域。我们的研究为“肠-脑”假说提供了有价值的细节，并为未来早期帕金森病干预的研究提出了一个有价值的帕金森病模型。