Abstract：
Aggregated deposits of the protein α-synuclein and depleting levels of dopamine in the brain correlate with Parkinson\'s disease development. Treatments often focus on replenishing dopamine in the brain; however, the brain might not be the only site requiring attention. Aggregates of α-synuclein appear to accumulate in the gut years prior to the onset of any motor symptoms. Enteroendocrine cells (specialized gut epithelial cells) may be the source of intestinal α-synuclein, as they natively express this protein. Enteroendocrine cells are constantly exposed to gut bacteria and their metabolites because they border the gut lumen. These cells also express the dopamine metabolic pathway and form synapses with vagal neurons, which innervate the gut and brain. Through this connection, Parkinson\'s disease pathology may originate in the gut and spread to the brain over time. Effective therapeutics to prevent this disease progression are lacking due to a limited understanding of the mechanisms by which α-synuclein aggregation occurs in the gut. We previously proposed a gut bacterial metabolic pathway responsible for the initiation of α-synuclein aggregation that is dependent on the oxidation of dopamine. Here, we develop a new tool, a laser-induced graphene-based electrochemical sensor chip, to track α-synuclein aggregation and dopamine level over time. Using these sensor chips, we evaluated diet-derived catechols dihydrocaffeic acid and caffeic acid as potential inhibitors of α-synuclein aggregation. Our results suggest that these molecules inhibit dopamine oxidation. We also found that these dietary catechols inhibit α-synuclein aggregation in STC-1 enteroendocrine cells. These findings are critical next steps to reveal new avenues for targeted therapeutics to treat Parkinson\'s disease, specifically in the context of functional foods that may be used to reshape the gut environment.
摘要：
蛋白质α-突触核蛋白的聚集沉积和大脑中多巴胺的消耗水平与帕金森病的发展相关。治疗通常集中在补充大脑中的多巴胺;然而，大脑可能不是唯一需要注意的地方。在任何运动症状发作之前，α-突触核蛋白的聚集体似乎在肠道中积累。肠内分泌细胞（特化肠上皮细胞）可能是肠道α-突触核蛋白的来源，因为它们天然表达这种蛋白质。肠内分泌细胞经常暴露于肠道细菌及其代谢物，因为它们与肠腔接壤。这些细胞还表达多巴胺代谢途径并与迷走神经元形成突触，支配肠道和大脑。通过这种联系,帕金森病的病理可能起源于肠道，并随着时间的推移扩散到大脑。由于对肠中发生α-突触核蛋白聚集的机制的理解有限,因此缺乏预防这种疾病进展的有效治疗剂。我们先前提出了一种肠道细菌代谢途径，该途径负责启动依赖于多巴胺氧化的α-突触核蛋白聚集。这里,我们开发了一种新工具，基于激光诱导石墨烯的电化学传感器芯片，随着时间的推移跟踪α-突触核蛋白聚集和多巴胺水平。使用这些传感器芯片，我们评估了饮食来源的儿茶酚二氢咖啡酸和咖啡酸作为α-突触核蛋白聚集的潜在抑制剂。我们的结果表明这些分子抑制多巴胺氧化。我们还发现这些膳食儿茶酚抑制STC-1肠内分泌细胞中的α-突触核蛋白聚集。这些发现是揭示靶向治疗帕金森病的新途径的关键下一步。特别是在可用于重塑肠道环境的功能性食品的背景下。
