CAG EXPANSION AFFECTS THE EXPRESSION OF MUTANT HUNTINGTIN IN THE HUNTINGTONS-DISEASE BRAIN
CAG EXPANSION AFFECTS THE EXPRESSION OF MUTANT HUNTINGTIN IN THE HUNTINGTONS-DISEASE BRAIN
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DOI：
10.1016/0896-6273(95)90106-x
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发表时间：
1995-11-01
期刊：
影响因子：
16.2
通讯作者：
DIFIGLIA, M
中科院分区：
文献类型：
--
作者：
ARONIN, N;CHASE, K;DIFIGLIA, M
亨廷顿基因中的三核苷酸重复（GAG）扩增导致亨廷顿病（HD）。在脑组织中，从HD杂合子与成人发病和更严重的临床青少年发病，其中发生最大的扩张，相当于强度野生型亨廷顿蛋白的突变蛋白质被检测到皮质突触体，表明突变物种的合成和运输与正常蛋白质的神经末梢。突变亨廷顿蛋白相对于野生型的大小增加与CAG重复扩增高度相关，从而将突变蛋白的电泳迁移率改变与其异常功能联系起来。突变亨廷顿蛋白出现在灰色和白色物质中，在受影响区域的表达没有差异。突变体蛋白质比野生型更广泛，在11个青少年的情况下，6解决了作为一个复杂的带，在DNA水平的体细胞镶嵌证据一致。因此，HD发病机制是由一种在脑中广泛表达且仅对某些神经元有害的异常蛋白质的功能获得引起的。
A trinucleotide repeat (GAG) expansion in the huntingtin gene causes Huntington's disease (HD). In brain tissue from HD heterozygotes with adult onset and more clinically severe juvenile onset, where the largest expansions occur, a mutant protein of equivalent intensity to wild-type huntingtin was detected in cortical synaptosomes, indicating that a mutant species is synthesized and transported with the normal protein to nerve endings. The increased size of mutant huntingtin relative to the wild type was highly correlated with CAG repeat expansion, thereby linking an altered electrophoretic mobility of the mutant protein to its abnormal function. Mutant huntingtin appeared in gray and white matter with no difference in expression in affected regions. The mutant protein was broader than the wild type and in 6 of 11 juvenile cases resolved as a complex of bands, consistent with evidence at the DNA level for somatic mosaicism. Thus, HD pathogenesis results from a gain of function by an aberrant protein that is widely expressed in brain and is harmful only to some neurons.