Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats
Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats
复制标题
帕金森病病理从大鼠胃肠道传播到大脑的直接证据
DOI：
10.1007/s00401-014-1343-6
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发表时间：
2014-12-01
影响因子：
12.7
通讯作者：
Li, Jia-Yi
中科院分区：
文献类型：
--
作者：
Holmqvist, Staffan;Chutna, Oldriska;Li, Jia-Yi
帕金森病（PD）的细胞标志是黑质多巴胺能神经元的丧失以及剩余神经元中富含α-突触核蛋白的路易体和路易神经突的形成。基于PD患者脑尸检后建立的路易体的地形分布，Braak及其同事假设路易病理在肠神经系统中启动并扩散到脑，表明α-突触核蛋白（路易体中的关键蛋白质组分）通过迷走神经主动逆行转运。然而，这一假设迄今尚未得到实验验证。在这里，我们使用含有不同形式的α-突触核蛋白（单体，寡聚体和纤维状）的人PD脑裂解物，以及在体内动物模型中的重组α-突触核蛋白来测试这一假设。我们证明，α-突触核蛋白存在于人PD脑裂解物和不同的重组α-突触核蛋白形式通过迷走神经运输，并在注射到肠壁后以时间依赖性的方式到达脑干中的迷走神经背侧运动核。在分化的神经母细胞瘤细胞系中使用活细胞成像，我们确定轴突运输的慢组分和快组分都参与聚集的α-突触核蛋白的运输。总之，我们在这里提供了第一个实验证据，不同的α-突触核蛋白形式可以从肠道传播到大脑，微管相关的运输参与了聚集的α-突触核蛋白在神经元中的易位。
The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of alpha-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of alpha-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of alpha-synuclein (monomeric, oligomeric and fibrillar), and recombinant alpha-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that alpha-synuclein present in the human PD brain lysate and distinct recombinant alpha-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated alpha-synuclein. In conclusion, we here provide the first experimental evidence that different alpha-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated alpha-synuclein in neurons.