Schilling G, Becher M W, Sharp A H, Jinnah H A, Duan K, Kotzuk J A, Slunt H H, Ratovitski T, Cooper J K, Jenkins N A, Copeland N G, Price D L, Ross C A, Borchelt D R
Department of Psychiatry, Division of Neuropathology, Johns Hopkins University, Baltimore, MD 21205-2196, USA.
Hum Mol Genet. 1999 Mar;8(3):397-407. doi: 10.1093/hmg/8.3.397.
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.
亨廷顿舞蹈病（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增引起。为深入了解HD的发病机制，我们构建了转基因小鼠，这些小鼠表达编码亨廷顿蛋白N端片段（171个氨基酸）的cDNA，该片段含有82、44或18个谷氨酰胺。表达相对低稳态水平且含有82个谷氨酰胺重复序列的N171亨廷顿蛋白（N171-82Q）的小鼠，在过早死亡前会出现行为异常，包括协调能力丧失、震颤、运动功能减退和步态异常。在表现出这些异常的小鼠中，在多个神经元群体中发现了弥漫性核标记、核内包涵体和神经突聚集物；用针对亨廷顿蛋白N端（氨基酸1-17）的抗体（AP194）检测，这些结构均呈免疫反应性。在表达N171-18Q的小鼠中未观察到这些行为或病理表型。这些发现与以下观点一致：具有重复序列扩增的亨廷顿蛋白N端片段对神经元有毒性，且N端片段易于形成核内包涵体和神经突聚集物。
