Huntington's disease (HD) is caused by polyglutamine (polyQ) expansions in huntingtin (HTT). Polyglutamine repeat lengths >35Q lead to neurodegeneration and longer repeats correspond to earlier symptom onset. HTT scaffolds kinesin-1 and dynein to a variety of vesicles and organelles directly and through adaptors. To characterize the effects of HTT polyQ expansions on axonal transport, we tracked BDNF vesicles, mitochondria, and lysosomes in neurons induced from an isogenic set of human stem cell lines with repeat lengths of 30, 45, 65, and 81Q. Mild and intermediate pathogenic polyQ expansions caused increased BDNF motility, while HTT-81Q misdirected BDNF towards the distal tip. In comparison, mitochondria and lysosome transport showed mild defects with polyQHTT. We next examined the effect of polyQHTT in combination with neuroinflammatory stress. Under stress, BDNF cargoes in HTT-30Q neurons were more processive. Stress in HTT-81Q resulted in a stark decrease in the number of BDNF cargoes. However, the few remaining BDNF cargoes displayed more frequent long-range motility in both directions. Under neuroinflammatory stress, lysosomes were more abundant in HTT-81Q neurons, and motile lysosomes moved less processively and had an anterograde bias while lysosomes in HTT-30Q where not strongly affected. To examine how HTT-polyQ expansions altered the motors and adaptors on vesicular cargoes, we isolated BDNF cargoes from neurons and quantified the proteins associated with them. BDNF-endosomes isolated from HTT-81Q neurons associated with 2.5 kinesin-1 and 3.9 HAP1 molecules on average, compared to 1.0 kinesin-1 and 1.0 HAP1 molecule for HTT-30Q neurons. Together, these results show that polyQ expansions in HTT cause aberrant motor and adaptor recruitment to cargoes, resulting in dysregulated transport and responses to neuroinflammatory stress.

中文翻译：

---

亨廷顿聚谷氨酰胺扩张通过干扰运动和适配器募集来误导轴突运输

亨廷顿病 (HD) 是由亨廷顿蛋白 (HTT) 中的聚谷氨酰胺 (polyQ) 扩增引起的。聚谷氨酰胺重复长度 >35Q 会导致神经变性，较长的重复对应于较早的症状发作。 HTT 直接或通过接头将驱动蛋白-1 和动力蛋白支架到各种囊泡和细胞器上。为了表征 HTT polyQ 扩展对轴突运输的影响，我们追踪了由一组重复长度为 30、45、65 和 81Q 的同基因人类干细胞系诱导的神经元中的 BDNF 囊泡、线粒体和溶酶体。轻度和中度致病性 PolyQ 扩张导致 BDNF 运动性增加，而 HTT-81Q 将 BDNF 误导至远端。相比之下，polyQHTT 的线粒体和溶酶体运输显示出轻微缺陷。接下来我们检查了 PolyQHTT 与神经炎症应激相结合的效果。在压力下，HTT-30Q 神经元中的 BDNF 负载更加活跃。 HTT-81Q 中的压力导致 BDNF 货物数量明显减少。然而，剩下的少数 BDNF 货物在两个方向上表现出更频繁的远程运动。在神经炎症应激下，HTT-81Q 神经元中的溶酶体更加丰富，运动性溶酶体的进行性移动较少，并且具有顺行性偏向，而 HTT-30Q 中的溶酶体则没有受到强烈影响。为了研究 HTT-polyQ 扩展如何改变囊泡货物上的马达和适配器，我们从神经元中分离了 BDNF 货物并量化了与其相关的蛋白质。从 HTT-81Q 神经元中分离出的 BDNF 内体平均与 2.5 个驱动蛋白-1 和 3.9 个 HAP1 分子相关，而 HTT-30Q 神经元则与 1.0 个驱动蛋白-1 和 1.0 个 HAP1 分子相关。总之，这些结果表明，HTT 中的 PolyQ 扩展会导致异常的运动和适配器招募到货物，从而导致运输失调和对神经炎症应激的反应。