α-Synuclein in gut endocrine cells and its implications for Parkinson's disease
α-Synuclein in gut endocrine cells and its implications for Parkinson's disease
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DOI：
10.1172/jci.insight.92295
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发表时间：
2017-06-15
期刊：
影响因子：
8
通讯作者：
Liddle, Rodger A.
中科院分区：
文献类型：
--
作者：
Chandra, Rashmi;Hiniker, Annie;Liddle, Rodger A.
帕金森病（Parkinson's disease，PD）是一种进行性神经退行性疾病，临床表现严重。在PD中，神经元死亡与称为路易体的神经元蛋白α-突触核蛋白的细胞内聚集体相关。虽然散发性PD的原因还不清楚，但大量的临床和病理证据表明，在肠神经中发现错误折叠的α-突触核蛋白，然后才出现在大脑中。这表明了一种模型，其中PD病理起源于肠道并通过细胞间朊病毒样传播扩散至中枢神经系统，使得错误折叠的α-突触核蛋白的转移引发受体细胞中天然α-突触核蛋白的错误折叠。我们最近发现，肠内分泌细胞（EECs），这是肠道上皮细胞的一部分，直接面对肠腔，也具有许多神经元样的特性，并连接到肠神经。在这份报告中，我们证明了α-突触核蛋白表达的EEC线，STC-1，和本地的小鼠和人类肠道的EEC。此外，含有α-突触核蛋白的EEC直接连接到含有α-突触核蛋白的神经，在肠和神经系统之间形成神经回路，其中肠腔中的毒素或其他环境影响可以影响EEC中的α-突触核蛋白折叠，从而开始错误折叠的α-突触核蛋白可以从肠上皮传播到大脑的过程。
Parkinson's disease (PD) is a progressive neurodegenerative disease with devastating clinical manifestations. In PD, neuronal death is associated with intracellular aggregates of the neuronal protein alpha-synuclein known as Lewy bodies. Although the cause of sporadic PD is not well understood, abundant clinical and pathological evidence show that misfolded alpha-synuclein is found in enteric nerves before it appears in the brain. This suggests a model in which PD pathology originates in the gut and spreads to the central nervous system via cell-to-cell prion-like propagation, such that transfer of misfolded alpha-synuclein initiates misfolding of native alpha-synuclein in recipient cells. We recently discovered that enteroendocrine cells (EECs), which are part of the gut epithelium and directly face the gut lumen, also possess many neuron-like properties and connect to enteric nerves. In this report, we demonstrate that alpha-synuclein is expressed in the EEC line, STC-1, and native EECs of mouse and human intestine. Furthermore, alpha-synuclein-containing EECs directly connect to alpha-synuclein-containing nerves, forming a neural circuit between the gut and the nervous system in which toxins or other environmental influences in the gut lumen could affect alpha-synuclein folding in the EECs, thereby beginning a process by which misfolded alpha-synuclein could propagate from the gut epithelium to the brain.