Chandra Rashmi, Hiniker Annie, Kuo Yien-Ming, Nussbaum Robert L, Liddle Rodger A
Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
Department of Pathology and.
JCI Insight. 2017 Jun 15;2(12). doi: 10.1172/jci.insight.92295.
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 α-synuclein known as Lewy bodies. Although the cause of sporadic PD is not well understood, abundant clinical and pathological evidence show that misfolded α-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 α-synuclein initiates misfolding of native α-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 α-synuclein is expressed in the EEC line, STC-1, and native EECs of mouse and human intestine. Furthermore, α-synuclein-containing EECs directly connect to α-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 α-synuclein folding in the EECs, thereby beginning a process by which misfolded α-synuclein could propagate from the gut epithelium to the brain.
帕金森病（PD）是一种具有毁灭性临床表现的进行性神经退行性疾病。在帕金森病中，神经元死亡与神经元蛋白α-突触核蛋白的细胞内聚集体（即路易小体）有关。尽管散发性帕金森病的病因尚不完全清楚，但大量临床和病理证据表明，错误折叠的α-突触核蛋白在出现在大脑之前就已在肠神经中被发现。这提示了一种模型，即帕金森病病理起源于肠道，并通过细胞间朊病毒样传播扩散到中枢神经系统，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，作为肠道上皮一部分且直接面对肠腔的肠内分泌细胞（EECs）也具有许多神经元样特性，并与肠神经相连。在本报告中，我们证明α-突触核蛋白在小鼠和人类肠道的EEC系STC-1以及天然EECs中表达。此外，含有α-突触核蛋白的EECs直接与含有α-突触核蛋白的神经相连，在肠道和神经系统之间形成一个神经回路，其中肠腔内的毒素或其他环境影响可能会影响EECs中α-突触核蛋白的折叠，从而启动一个过程，通过该过程错误折叠的α-突触核蛋白可能从肠道上皮传播到大脑。
