Enhanced Sensitivity of Striatal Neurons to Axonal Transport Defects Induced by Mutant Huntingtin
Enhanced Sensitivity of Striatal Neurons to Axonal Transport Defects Induced by Mutant Huntingtin
复制标题
DOI：
10.1523/jneurosci.4144-08.2008
复制
发表时间：
2008-12-10
影响因子：
5.3
通讯作者：
Goldstein, Lawrence S. B.
中科院分区：
文献类型：
--
作者：
Her, Lu-Shiun;Goldstein, Lawrence S. B.
亨廷顿氏病（HD）是一种常染色体显性神经退行性疾病，与亨廷顿蛋白中聚q（聚谷氨酰胺）扩增有关。虽然HD患者普遍存在脑萎缩，但纹状体是受影响最严重的区域。据报道，亨廷顿蛋白的缺失或突变形式会破坏果蝇、鱿鱼和小鼠的快速轴突运输。然而，之前的研究并没有解决突变的亨廷顿蛋白是否影响全局轴突运输或仅仅影响一部分货物，也没有解决纹状体神经元是否对亨廷顿蛋白介导的缺陷优先敏感。我们使用淀粉样蛋白前体蛋白(APP)-黄色荧光蛋白和脑源性神经营养因子(BDNF)-mCherry融合蛋白作为亨廷顿蛋白改变时快速轴突转运的标记。我们发现，在症状前携带150Q亨廷顿蛋白敲入突变的纯合子突变小鼠中，纹状体和海马神经元的APP和BDNF的运动受到损害，而皮质神经元则没有。此外，亨廷顿蛋白的缺失会破坏APP轴突运输，而野生型而非突变型亨廷顿蛋白的过表达会增强APP在所有三种类型的神经元中的运输。这些数据表明，野生型亨廷顿蛋白在快速轴突运输中的功能缺失在HD细胞类型特异性缺陷的发展中起着重要作用。
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease linked to a polyQ ( polyglutamine) expansion in the huntingtin protein. Although general brain atrophy is found in HD patients, the striatum is the most severely affected region. Loss or mutant forms of huntingtin were reported to disrupt fast axonal transport in Drosophila, squid, and mice. However, previous work did not resolve whether mutant huntingtin affects global axonal transport or only a subset of cargoes, nor did it resolve whether striatal neurons are preferentially sensitive to huntingtin-mediated defects. We used amyloid precursor protein (APP)-yellow fluorescent protein and brain-derived neurotrophic factor (BDNF)-mCherry fusion proteins as markers for fast axonal transport when huntingtin is altered. We found that movement of APP and BDNF is impaired in striatal and hippocampal, but not cortical, neurons from presymptomatic homozygous mutant mice carrying 150Q huntingtin knock-in mutations. In addition, loss of huntingtin disrupts APP axonal transport, whereas overexpression of wild-type, but not mutant, huntingtin enhances APP transport in all three types of neurons tested. These data suggest that a loss of wild-type huntingtin function in fast axonal transport plays important roles in the development of cell-type-specific defects in HD.