Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mice
Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mice
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Hap1 缺失选择性促进亨廷顿病小鼠纹状体变性
DOI：
10.1073/pnas.2002283117
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发表时间：
2020-08-18
影响因子：
11.1
通讯作者：
Li, Xiao-Jiang
中科院分区：
文献类型：
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作者：
Liu, Qiong;Cheng, Siying;Li, Xiao-Jiang
亨廷顿病（HD）是研究选择性神经变性的理想模型，因为亨廷顿病患者大脑纹状体中普遍表达的亨廷顿蛋白（HTT）中扩增的多q重复序列导致了优先性神经变性。在这里，我们报道了腺相关病毒（AAV）转导介导的Hap1的缺失，Hap1是第一个被发现的亨廷顿蛋白相关蛋白，在成年HD敲入（KI）小鼠大脑中导致纹状体选择性神经元丢失。此外，Hap1消耗通过AAV转导介导的神经元损失需要突变HTT的存在。Rhes是一种在纹状体中富集的GTPase，它可以使突变的HTT聚合以介导神经毒性，当Hap1缺乏时，Rhes可以结合更多的n端HTT。同样，当HAP1缺失时，HD KI小鼠纹状体中出现更多可溶性和聚合的n端HTT。我们的研究结果表明，Rhes和Hap1以及细胞应激都有助于HD患者的优先神经退行性变，强调了多因素参与选择性神经退行性变。
Huntington disease (HD) is an ideal model for investigating selective neurodegeneration, as expanded polyQ repeats in the ubiquitously expressed huntingtin (HTT) cause the preferential neurodegeneration in the striatum of the HD patient brains. Here we report that adeno-associated virus (AAV) transduction-mediated depletion of Hap1, the first identified huntingtin-associated protein, in adult HD knock-in (KI) mouse brains leads to selective neuronal loss in the striatum. Further, Hap1 depletion-mediated neuronal loss via AAV transduction requires the presence of mutant HTT. Rhes, a GTPase that is enriched in the striatum and sumoylates mutant HTT to mediate neurotoxicity, binds more N-terminal HTT when Hap1 is deficient. Consistently, more soluble and sumoylated N-terminal HTT is presented in HD KI mouse stria-tum when HAP1 is absent. Our findings suggest that both Rhes and Hap1 as well as cellular stress contribute to the preferential neurodegeneration in HD, highlighting the involvement of multi-ple factors in selective neurodegeneration.