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两亲性肽对亨廷顿舞蹈病寡聚体组装过程的纳米级洞察

Nanoscopic Insights of Amphiphilic Peptide against the Oligomer Assembly Process to Treat Huntington's Disease.

作者信息

He Ruei-Yu, Lai Xiang-Me, Sun Chia-Sui, Kung Te-Shien, Hong Jhu-Ying, Jheng Yu-Song, Liao Wei-Neng, Chen Jen-Kun, Liao Yung-Feng, Tu Pang-Hsien, Huang Joseph Jen-Tse

机构信息

Institute of Chemistry Academia Sinica Taipei 11529 Taiwan.

Institute of Biomedical Sciences Academia Sinica Taipei 11529 Taiwan.

出版信息

Adv Sci (Weinh). 2019 Dec 9;7(2):1901165. doi: 10.1002/advs.201901165. eCollection 2020 Jan.

DOI:10.1002/advs.201901165
PMID:31993280
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6974936/
Abstract

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.

摘要

找到一种有效的治疗方案是包括亨廷顿舞蹈症（HD）在内的各种神经退行性疾病的迫切需求。由于在体内观察突变型亨廷顿蛋白（mHtt）的动态聚集和寡聚化过程存在困难，在分子蛋白水平评估潜在药物通常受到限制。通过结合基于寿命的荧光显微镜技术和生物物理工具，结果表明，一种设计的两亲性肽在早期靶向mHtt，可在纳米尺度上扰乱寡聚体组装过程，抑制mHtt的淀粉样特性，使mHtt的寡聚体和/或聚集体发生构象转变，并改善mHtt在细胞和HD小鼠模型中诱导的神经损伤和聚集。还发现这种两亲性肽能够通过鼻内给药转运到大脑并挽救记忆缺陷，表明其在体内的靶向特异性。总之，提供了一个生物光子平台来详细研究寡聚化/聚集过程，这为亨廷顿舞蹈症靶向治疗剂的设计和效果提供了见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/6163f7c2f356/ADVS-7-1901165-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/f8d45ad6ae7c/ADVS-7-1901165-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/ecb7de33021a/ADVS-7-1901165-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/563b3ed8bd4d/ADVS-7-1901165-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/6886ae8e978c/ADVS-7-1901165-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/6163f7c2f356/ADVS-7-1901165-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/f8d45ad6ae7c/ADVS-7-1901165-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/ecb7de33021a/ADVS-7-1901165-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/563b3ed8bd4d/ADVS-7-1901165-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/6886ae8e978c/ADVS-7-1901165-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c56/6974936/6163f7c2f356/ADVS-7-1901165-g004.jpg

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