Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes
Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes
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DOI：
10.1093/hmg/ddq038
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发表时间：
2010-05-01
影响因子：
3.5
通讯作者：
Nussbaum, Robert L.
中科院分区：
文献类型：
--
作者：
Kuo, Yien-Ming;Li, Zhishan;Nussbaum, Robert L.
帕金森病（PD）是一种神经退行性疾病，在胃肠道中具有运动和非运动体征，包括吞咽困难、胃轻瘫、胃肠道通过时间延长、便秘和排便困难。胃肠道功能障碍通常先于运动症状数十年。大多数PD是散发性的，病因不明，但一小部分是家族性的。在家族性PD中，一小部分是由SNCA中的错义（A53 T、A30 P和E46 K）和拷贝数突变引起的，SNCA编码α-突触核蛋白，路易体的主要蛋白成分，PD神经元中发现的特异性蛋白质聚集体。我们着手开发转基因小鼠表达突变体α-突触核蛋白（A53 T或A30 P）从插入一个完整的人类SNCA基因作为模型的家族性疾病。A53 T和A30 P系在3月龄时肠神经系统（ENS）功能和ENS神经节中的突触核蛋白免疫反应性聚集体均显示出强烈的异常。A53 T细胞系也有异常的运动行为，但均未显示心脏自主神经异常、嗅觉功能障碍、多巴胺能神经递质缺乏、路易体包涵体或神经变性。这些动物重现了在人PD中观察到的早期胃肠道异常。这些动物还充当体内系统，在其中研究用于逆转神经功能障碍的疗法，所述神经功能障碍在其最早阶段靶向α-突触核蛋白毒性。
Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor signs in the gastrointestinal tract that include dysphagia, gastroparesis, prolonged gastrointestinal transit time, constipation and difficulty with defecation. The gastrointestinal dysfunction commonly precedes the motor symptoms by decades. Most PD is sporadic and of unknown etiology, but a fraction is familial. Among familial forms of PD, a small fraction is caused by missense (A53T, A30P and E46K) and copy number mutations in SNCA which encodes alpha-synuclein, a primary protein constituent of Lewy bodies, the pathognomonic protein aggregates found in neurons in PD. We set out to develop transgenic mice expressing mutant alpha-synuclein (either A53T or A30P) from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines show robust abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also has abnormal motor behavior but neither demonstrates cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions or neurodegeneration. These animals recapitulate the early gastrointestinal abnormalities seen in human PD. The animals also serve as an in vivo system in which to investigate therapies for reversing the neurological dysfunction that target alpha-synuclein toxicity at its earliest stages.