Gastrointestinal dysfunction can affect Parkinson’s disease (PD) patients long before the onset of motor symptoms. However, little is known about the relationship between gastrointestinal abnormalities and the development of PD. Contrary to other animal models, the human A53T alpha-synuclein (αS) transgenic mice, Line G2–3, develops αS-driven neurological and motor impairments after 9 months of age, displaying a long presymptomatic phase free of central nervous system (CNS) dysfunction. To determine whether this line can be suitable to study constipation as it occurs in prodromal PD, gastrointestinal functionality was assessed in young mice through a multidisciplinary approach, based on behavioral and biochemical analysis combined with electrophysiological recordings of mouse intestinal preparations. We found that the A53T αS mice display remarkable signs of gastrointestinal dysfunction that precede motor abnormalities and αS pathology in the CNS by at least 6 months. Young αS mice show a drastic delay in food transit along the gastrointestinal tract, of almost 2 h in 3 months old mice that increased to more than 3 h at 6 months. Such impairment was associated with abnormal formation of stools that resulted in less abundant but longer pellets excreted, suggesting a deficit in the intestinal peristalsis. In agreement with this, electrically evoked contractions of the colon, but not of the ileum, showed a reduced motor response in both longitudinal and circular muscle layers in αS mice already at 3 months of age, that was mainly due to an impaired cholinergic transmission of the underlying enteric nervous system. Interestingly, the presence of insoluble and aggregated αS was found in enteric neurons in both myenteric and submucosal plexi only in the colon of 3 months old αS mice, but not in the small intestine, and exacerbated with age, mimicking the increase in transit delay and the contraction deficit showed by behavioral and electrical recordings data. Gastrointestinal dysfunction in A53T αS mice represents an early sign of αS-driven pathology without concomitant CNS involvement. We believe that this model can be very useful to study disease-modifying strategies that could extend the prodromal phase of PD and halt αS pathology from reaching the brain.

中文翻译：

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在α-突触核蛋白病小鼠模型中，便秘、结肠收缩缺陷和结肠内α-突触核蛋白包涵体先于运动异常和中枢神经系统的神经退行性变

胃肠功能障碍可以在运动症状出现之前很久就影响帕金森病 (PD) 患者。然而，关于胃肠道异常与PD发展之间的关系知之甚少。与其他动物模型相反，人类 A53T α-突触核蛋白 (αS) 转基因小鼠 G2-3 系在 9 个月大后出现αS 驱动的神经和运动障碍，表现出长期无中枢神经系统 (CNS) 的症状前阶段功能障碍。为了确定这条线是否适合研究便秘，因为它发生在前驱 PD 中，基于行为和生化分析以及小鼠肠道制剂的电生理记录，通过多学科方法对年轻小鼠的胃肠道功能进行了评估。我们发现，A53T αS 小鼠在中枢神经系统运动异常和αS 病变之前至少 6 个月表现出明显的胃肠功能障碍迹象。年轻的 αS 小鼠在胃肠道的食物运输中表现出明显的延迟，在 3 个月大的小鼠中几乎 2 小时，而在 6 个月时增加到 3 小时以上。这种损伤与粪便的异常形成有关，导致排出的颗粒较少但较长，表明肠道蠕动不足。与此一致的是，在 3 个月大的 αS 小鼠中，结肠而非回肠的电诱发收缩显示出纵向和圆形肌肉层的运动反应降低，这主要是由于胆碱能传递受损。潜在的肠神经系统。有趣的是，仅在 3 个月大的 αS 小鼠的结肠中发现不溶性和聚集的 αS 存在于肠肌层和黏膜下丛的肠神经元中，但在小肠中没有，并且随着年龄的增长而加剧，模拟运输延迟和收缩的增加行为和电子记录数据显示的缺陷。A53T αS 小鼠的胃肠功能障碍代表了没有伴随 CNS 受累的 αS 驱动病理学的早期迹象。我们相信，该模型对于研究可以延长 PD 前驱期并阻止 αS 病理到达大脑的疾病缓解策略非常有用。模仿行为和电子记录数据显示的运输延迟增加和收缩不足。A53T αS 小鼠的胃肠功能障碍代表了没有伴随 CNS 受累的 αS 驱动病理学的早期迹象。我们相信，该模型对于研究可以延长 PD 前驱期并阻止 αS 病理到达大脑的疾病缓解策略非常有用。模仿行为和电子记录数据显示的运输延迟增加和收缩不足。A53T αS 小鼠的胃肠功能障碍代表了没有伴随 CNS 受累的 αS 驱动病理学的早期迹象。我们相信，该模型对于研究可以延长 PD 前驱期并阻止 αS 病理到达大脑的疾病缓解策略非常有用。