Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats
Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats
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DOI：
10.1007/s00401-019-02040-w
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发表时间：
2019-10-01
影响因子：
12.7
通讯作者：
Borghammer, Per
中科院分区：
文献类型：
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作者：
Van Den Berge, Nathalie;Ferreira, Nelson;Borghammer, Per
内源性α -突触核蛋白（asyn）转化为病理性的富集异步聚集体是帕金森病（PD）的一个标志。这些包涵体可在中枢和肠神经系统（ENS）中检测到。此外，胃肠道症状可在PD诊断前20年出现。双重打击假说假设病理性共济聚集开始于ENS，并逆行扩散到大脑。在本研究中，我们通过将预制的肌酰胺原纤维直接注射到野生型大鼠和人肌酰胺水平过高的转基因大鼠的十二指肠壁来验证这一假设。我们通过在注射后的早期时间点进行免疫组织化学，提供了细菌人工染色体（BAC）转基因大鼠模型关于病理性异构体沿着副交感神经和交感神经通路到脑干的初始传播的细致表征。在交感神经和副交感神经通路的所有关键结构（ENS、自主神经节、脊髓中外侧核（IML）、心脏、迷走神经背侧运动核和蓝斑（LC））中观察到诱导病理，并在注射后持续至少4个月。相比之下，野生型大鼠和车辆注射BAC大鼠均未检测到异型繁殖。内颞叶、左心室和心脏的病理表现表明病理的跨突触扩散。此外，胃和心脏中观察到的异构体包涵体可能表明在最初的逆行扩散后继发的逆行传播。综上所述，在BAC大鼠模型中，asyn的突触间传播完全符合PD发病的“体优先假说”。据我们所知，这是第一个证明异步传播到心脏的动物模型，也是第一个通过迷走神经双向异步传播的迹象，即十二指肠-脑干-胃。BAC大鼠模型对于双重打击假说的详细机制研究以及针对胃肠道早期病理的疾病修饰疗法的研究非常有价值。
The conversion of endogenous alpha-synuclein (asyn) to pathological asyn-enriched aggregates is a hallmark of Parkinson's disease (PD). These inclusions can be detected in the central and enteric nervous system (ENS). Moreover, gastrointestinal symptoms can appear up to 20 years before the diagnosis of PD. The dual-hit hypothesis posits that pathological asyn aggregation starts in the ENS, and retrogradely spreads to the brain. In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat model with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pathways (ENS, autonomic ganglia, intermediolateral nucleus of the spinal cord (IML), heart, dorsal motor nucleus of the vagus, and locus coeruleus (LC)) and persisted for at least 4 months post-injection. In contrast, asyn propagation was not detected in wild-type rats, nor in vehicle-injected BAC rats. The presence of pathology in the IML, LC, and heart indicate trans-synaptic spread of the pathology. Additionally, the observed asyn inclusions in the stomach and heart may indicate secondary anterograde propagation after initial retrograde spreading. In summary, trans-synaptic propagation of asyn in the BAC rat model is fully compatible with the "body-first hypothesis" of PD etiopathogenesis. To our knowledge, this is the first animal model evidence of asyn propagation to the heart, and the first indication of bidirectional asyn propagation via the vagus nerve, i.e., duodenum-to-brainstem-to-stomach. The BAC rat model could be very valuable for detailed mechanistic studies of the dual-hit hypothesis, and for studies of disease modifying therapies targeting early pathology in the gastrointestinal tract.