Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin
Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin
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DOI：
10.1093/hmg/8.3.397
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发表时间：
1999-03-01
影响因子：
3.5
通讯作者：
Borchelt, DR
中科院分区：
文献类型：
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作者：
Schilling, G;Becher, MW;Borchelt, DR
亨廷顿病(HD)是一种遗传性神经退行性疾病，由亨廷顿蛋白N端谷氨酰胺重复序列的扩张引起。为了深入了解HD的发病机制，我们培育了一只表达亨廷顿蛋白N端片段(171个氨基酸)的转基因小鼠，该小鼠含有82、44或18个谷氨酸，表达相对较低的稳定水平的具有82个谷氨酰胺重复(N171-82Q)的亨廷顿蛋白，小鼠在过早死亡之前会出现行为异常，包括协调性丧失、震颤、运动减少和步态异常。在表现这些异常的小鼠中，在多个神经元群体中发现了弥漫性核标记、核内包涵体和神经元聚集体，它们都与亨廷顿蛋白(AP194)的N端(氨基酸1-17)抗体呈免疫反应。在表达N171-18Q的小鼠中没有发现这些行为或病理表型，这些发现与亨廷顿蛋白重复扩张的N-端片段对神经元有毒，以及N-端片段容易形成核内包涵体和神经性聚集体的观点一致。
Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines, Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q, These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.