Huntington’s disease (HD) is characterized by protein inclusions and loss of striatal neurons which result from expanded CAG repeats in the poly-glutamine (polyQ) region of the huntingtin (HTT) gene. Both polyQ expansion and loss of HTT have been shown to cause axonal transport defects. While studies show that HTT is important for vesicular transport within axons, the cargo that HTT transports to/from synapses remain elusive. Here, we show that HTT is present with a class of Rab4-containing vesicles within axons in vivo. Reduction of HTT perturbs the bi-directional motility of Rab4, causing axonal and synaptic accumulations. In-vivo dual-color imaging reveal that HTT and Rab4 move together on a unique putative vesicle that may also contain synaptotagmin, synaptobrevin, and Rab11. The moving HTT-Rab4 vesicle uses kinesin-1 and dynein motors for its bi-directional movement within axons, as well as the accessory protein HIP1 (HTT-interacting protein 1). Pathogenic HTT disrupts the motility of HTT-Rab4 and results in larval locomotion defects, aberrant synaptic morphology, and decreased lifespan, which are rescued by excess Rab4. Consistent with these observations, Rab4 motility is perturbed in iNeurons derived from human Huntington’s Disease (HD) patients, likely due to disrupted associations between the polyQ-HTT-Rab4 vesicle complex, accessory proteins, and molecular motors. Together, our observations suggest the existence of a putative moving HTT-Rab4 vesicle, and that the axonal motility of this vesicle is disrupted in HD causing synaptic and behavioral dysfunction. These data highlight Rab4 as a potential novel therapeutic target that could be explored for early intervention prior to neuronal loss and behavioral defects observed in HD.

中文翻译：

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过量的Rab4可以挽救因亨廷顿舞蹈病引起的HTT-Rab4轴突运输缺陷引起的突触和行为功能障碍。

亨廷顿舞蹈病（HD）的特征是蛋白质包涵体和纹状体神经元的丢失，这是由于亨廷顿（HTT）基因的聚谷氨酰胺（polyQ）区域中的CAG重复序列扩大所致。polyQ膨胀和HTT的损失均已显示会导致轴突运输缺陷。虽然研究表明，HTT对于轴突内的囊泡运输很重要，但HTT往返于突触的货物仍然难以捉摸。在这里，我们显示HTT与体内轴突内一类含Rab4的囊泡一起存在。HTT的减少扰乱了Rab4的双向运动，导致轴突和突触积累。体内双色成像显示，HTT和Rab4在一个独特的假定囊泡上一起移动，该囊泡中可能还含有突触结合蛋白，突触短纤维蛋白和Rab11。运动的HTT-Rab4囊泡使用kinesin-1和dynein马达进行轴突内的双向运动，以及辅助蛋白HIP1（与HTT相互作用的蛋白1）。致病性HTT破坏了HTT-Rab4的运动，并导致幼虫运动缺陷，异常的突触形态和寿命缩短，这些可以通过过量的Rab4来挽救。与这些观察结果一致，源自人亨廷顿病（HD）患者的iNeurons干扰了Rab4运动，这可能是由于polyQ-HTT-Rab4囊泡复合物，辅助蛋白和分子运动之间的关联被破坏了。在一起，我们的观察结果表明存在假定的移动的HTT-Rab4囊泡，并且该囊泡的轴突运动在HD中被破坏，导致突触和行为功能障碍。