Deletion of the huntingtin proline-rich region does not significantly affect normal huntingtin function in mice.
Deletion of the huntingtin proline-rich region does not significantly affect normal huntingtin function in mice.
复制标题
亨廷顿蛋白含量丰富的区域的缺失不会显着影响小鼠的正常亨廷顿功能。
DOI：
10.3233/jhd-2012-120016
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Zeitlin SO
中科院分区：
文献类型：
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作者：
Neveklovska M;Clabough EB;Steffan JS;Zeitlin SO
亨廷顿蛋白是由亨廷顿氏病基因编码的蛋白质，其N-末端含有一段在亨廷顿氏病中扩展的多聚谷氨酰胺残基。在脊椎动物中，多聚谷氨酰胺片段的两侧是两个保守的蛋白质结构域：N1-17结构域和富含脯氨酸的区域（PRR）。PRR可以调节相邻的聚谷氨酰胺片段的结构，并且是几种相互作用蛋白质的结合位点。为了确定PRR在亨廷顿蛋白功能中的作用，我们产生了小鼠亨廷顿病基因同源物的敲入等位基因，其表达缺乏PRR的全长正常亨廷顿蛋白。亨廷顿蛋白PRR缺失的纯合子小鼠以正常的孟德尔频率出生，这表明PRR在胚胎发育期间对于基本的亨廷顿蛋白功能不是必需的。此外，成年纯合突变体在一般运动功能和运动学习方面与野生型对照没有表现出任何显著差异。然而，18个月大的男性，而不是女性，纯合子PRR缺失突变体表现出的Morris水任务的赤字，这表明年龄依赖性的空间学习和记忆可能会受到影响，在性别特异性的方式由亨廷顿蛋白PRR缺失。
The N-terminus of Huntingtin, the protein encoded by the Huntington’s disease gene, contains a stretch of polyglutamine residues that is expanded in Huntington’s disease. The polyglutamine stretch is flanked by two conserved protein domains in vertebrates: an N1-17 domain, and a proline-rich region (PRR). The PRR can modulate the structure of the adjacent polyglutamine stretch, and is a binding site for several interacting proteins. To determine the role of the PRR in Huntingtin function, we have generated a knock-in allele of the mouse Huntington’s disease gene homolog that expresses full-length normal huntingtin lacking the PRR. Mice that are homozygous for the huntingtin PRR deletion are born at the normal Mendelian frequency, suggesting that the PRR is not required for essential huntingtin functions during embryonic development. Moreover, adult homozygous mutants did not exhibit any significant differences from wild-type controls in general motor function and motor learning. However, 18 month-old male, but not female, homozygous PRR deletion mutants exhibited deficits in the Morris water task, suggesting that age-dependent spatial learning and memory may be affected in a sex-specific fashion by the huntingtin PRR deletion.