Finding an effective therapeutic regimen is an urgent demand for various neurodegenerative disorders including Huntington's disease (HD). For the difficulties in observing the dynamic aggregation and oligomerization process of mutant Huntingtin (mHtt) in vivo, the evaluation of potential drugs at the molecular protein level is usually restricted. By combing lifetime-based fluorescence microscopies and biophysical tools, it is showcased that a designed amphiphilic peptide, which targets the mHtt at an early stage, can perturb the oligomer assembly process nanoscopically, suppress the amyloid property of mHtt, conformationally transform the oligomers and/or aggregates of mHtt, and ameliorate mHtt-induced neurological damage and aggregation in cell and HD mouse models. It is also found that this amphiphilic peptide is able to transport to the brain and rescue the memory deficit through intranasal administration, indicating its targeting specificity in vivo. In summary, a biophotonic platform is provided to investigate the oligomerization/aggregation process in detail that offers insight into the design and effect of a targeted therapeutic agent for Huntington's disease.

中文翻译：

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两亲性肽对治疗亨廷顿病的寡聚物组装过程的纳米观察。


寻找有效的治疗方案是包括亨廷顿病（HD）在内的各种神经退行性疾病的迫切需求。由于观察突变型亨廷顿蛋白（mHtt）体内动态聚集和寡聚过程的困难，在分子蛋白水平上对潜在药物的评价通常受到限制。通过结合基于寿命的荧光显微镜和生物物理工具，表明设计的两亲性肽在早期阶段就以 mHtt 为目标，可以在纳米尺度上扰乱低聚物组装过程，抑制 mHtt 的淀粉样蛋白特性，对低聚物进行构象转变和/或 mHtt 聚集体，并改善细胞和 HD 小鼠模型中 mHtt 诱导的神经损伤和聚集。研究还发现，这种两亲性肽能够通过鼻内给药转运至大脑并挽救记忆缺陷，这表明其在体内具有靶向特异性。总之，提供了一个生物光子平台来详细研究寡聚/聚集过程，从而深入了解亨廷顿病靶向治疗剂的设计和效果。