Rota Lucia, Pellegrini Carolina, Benvenuti Laura, Antonioli Luca, Fornai Matteo, Blandizzi Corrado, Cattaneo Antonino, Colla Emanuela
1Bio@SNS Laboratory, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy.
2Department of Pharmacy, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
Transl Neurodegener. 2019 Feb 6;8:5. doi: 10.1186/s40035-019-0146-z. eCollection 2019.
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.
胃肠功能障碍在帕金森病（PD）患者运动症状出现之前很久就可能对其产生影响。然而，关于胃肠异常与PD发生发展之间的关系，人们了解甚少。与其他动物模型不同，人A53Tα-突触核蛋白（αS）转基因小鼠品系G2-3在9月龄后会出现αS驱动的神经和运动障碍，在很长的无症状期内无中枢神经系统（CNS）功能障碍。
为了确定该品系是否适合研究前驱期PD患者出现的便秘情况，通过多学科方法对幼鼠的胃肠功能进行评估，该方法基于行为和生化分析，并结合小鼠肠道标本的电生理记录。
我们发现A53TαS小鼠在运动异常和CNS中的αS病理改变出现之前至少6个月就表现出明显的胃肠功能障碍迹象。幼年αS小鼠胃肠道食物转运明显延迟，3月龄小鼠延迟近2小时，6月龄时增加到3小时以上。这种损害与粪便异常形成有关，导致排出的粪便量减少但长度增加，提示肠道蠕动不足。与此一致的是，在3月龄的αS小鼠中，结肠（而非回肠）的电诱发收缩在纵行和环行肌层均显示运动反应降低，这主要是由于基础肠神经系统的胆碱能传递受损。有趣的是，仅在3月龄αS小鼠的结肠肌间神经丛和黏膜下神经丛的肠神经元中发现了不溶性聚集αS，小肠中未发现，且随年龄增长而加剧，这与行为和电记录数据显示的转运延迟增加和收缩缺陷一致。
A53TαS小鼠的胃肠功能障碍是αS驱动病理改变的早期迹象，且无CNS受累。我们认为该模型对于研究可延长PD前驱期并阻止αS病理改变累及大脑的疾病修饰策略非常有用。
