α-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits.
α-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits.
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DOI：
10.1016/j.nbd.2012.04.009
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发表时间：
2012-08
影响因子：
6.1
通讯作者：
Isacson O
中科院分区：
文献类型：
--
作者：
Hallett PJ;McLean JR;Kartunen A;Langston JW;Isacson O
在研究过度表达人类野生型 α-突触核蛋白（Thy1-ASO，ASO）的转基因小鼠以治疗典型的脑 α-突触核蛋白病和中枢神经系统神经病理学时，我们观察到胃肠道和其他外周器官的渐进性功能变化。一项更系统的研究表明，ASO 小鼠的胃肠道在 9-12 个月大时表现出严重的扩张和大肠阻塞。功能评估表明，与野生型同窝小鼠相比，ASO 小鼠的粪便含水量和粪便颗粒排出量减少，整个肠道转运时间增加，这表明存在便秘，这是帕金森病 (PD) 患者常见的症状。 12 个月大的 ASO 小鼠食物摄入量增加，体重下降，表明代谢异常。死后组织学分析表明，人 α-突触核蛋白在轴突纤维、肠神经系统的偶尔细胞体以及 ASO 小鼠的心脏中强烈表达。还观察到蛋白酶 K 不溶性 α-突触核蛋白的积累，这让人想起帕金森病中的神经退行性过程。我们在此记录的 ASO 小鼠的功能和病理变化可能与特发性和 α-突触核蛋白介导的 PD 遗传形式中也出现的自主神经缺陷有关。这些实验数据为 PD 和相关 α-突触核蛋白病的自主神经变化的治疗模型提供了基础。
While studying transgenic mice that overexpress human wildtype alpha-synuclein (Thy1-ASO, ASO) for typical brain alpha-synucleinopathy and central nervous system neuropathology, we observed progressive functional changes in the gastrointestinal and other peripheral organs. A more systematic study revealed that the gastrointestinal tract in ASO mice showed severe distension and blockage of the large intestine by 9–12 months of age. Functional assessments demonstrated a reduction in fecal water content and fecal pellet output, and increased whole gut transit time, in ASO mice compared to wildtype littermates, indicative of constipation, a symptom commonly reported by Parkinson's disease (PD) patients. Food intake was increased and body weight was decreased in 12 month old ASO mice, suggestive of metabolic abnormalities. Post-mortem histological analyses showed that human alpha-synuclein protein was robustly expressed in axonal fibers and in occasional cell bodies of the enteric nervous system, and in the heart of ASO mice. Accumulation of proteinase-K insoluble alpha-synuclein, reminiscent of neurodegenerative processes in PD was also observed. The functional and pathological changes we document here in ASO mice could relate to the autonomic deficits also seen in idiopathic and alpha-synuclein-mediated genetic forms of PD. These experimental data provide a foundation for therapeutic modeling of autonomic changes in PD and related alpha-synucleinopathies.