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Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds

Author

Listed:
  • Zhaoyang Li

    (Fudan University)

  • Cen Wang

    (Fudan University)

  • Ziying Wang

    (Fudan University)

  • Chenggang Zhu

    (Fudan University)

  • Jie Li

    (National Facility for Protein Science in Shanghai)

  • Tian Sha

    (Fudan University)

  • Lixiang Ma

    (Fudan University)

  • Chao Gao

    (Fudan University)

  • Yi Yang

    (University of Plymouth)

  • Yimin Sun

    (Fudan University)

  • Jian Wang

    (Fudan University)

  • Xiaoli Sun

    (Fudan University)

  • Chenqi Lu

    (Fudan University)

  • Marian Difiglia

    (Massachusetts General Hospital)

  • Yanai Mei

    (Fudan University)

  • Chen Ding

    (Fudan University)

  • Shouqing Luo

    (University of Plymouth)

  • Yongjun Dang

    (Fudan University)

  • Yu Ding

    (Fudan University)

  • Yiyan Fei

    (Fudan University)

  • Boxun Lu

    (Fudan University)

Abstract

Accumulation of mutant proteins is a major cause of many diseases (collectively called proteopathies), and lowering the level of these proteins can be useful for treatment of these diseases. We hypothesized that compounds that interact with both the autophagosome protein microtubule-associated protein 1A/1B light chain 3 (LC3)1 and the disease-causing protein may target the latter for autophagic clearance. Mutant huntingtin protein (mHTT) contains an expanded polyglutamine (polyQ) tract and causes Huntington’s disease, an incurable neurodegenerative disorder2. Here, using small-molecule-microarray-based screening, we identified four compounds that interact with both LC3 and mHTT, but not with the wild-type HTT protein. Some of these compounds targeted mHTT to autophagosomes, reduced mHTT levels in an allele-selective manner, and rescued disease-relevant phenotypes in cells and in vivo in fly and mouse models of Huntington’s disease. We further show that these compounds interact with the expanded polyQ stretch and could lower the level of mutant ataxin-3 (ATXN3), another disease-causing protein with an expanded polyQ tract3. This study presents candidate compounds for lowering mHTT and potentially other disease-causing proteins with polyQ expansions, demonstrating the concept of lowering levels of disease-causing proteins using autophagosome-tethering compounds.

Suggested Citation

  • Zhaoyang Li & Cen Wang & Ziying Wang & Chenggang Zhu & Jie Li & Tian Sha & Lixiang Ma & Chao Gao & Yi Yang & Yimin Sun & Jian Wang & Xiaoli Sun & Chenqi Lu & Marian Difiglia & Yanai Mei & Chen Ding & , 2019. "Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds," Nature, Nature, vol. 575(7781), pages 203-209, November.
  • Handle: RePEc:nat:nature:v:575:y:2019:i:7781:d:10.1038_s41586-019-1722-1
    DOI: 10.1038/s41586-019-1722-1
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    Cited by:

    1. Chang Hoon Ji & Hee Yeon Kim & Min Ju Lee & Ah Jung Heo & Daniel Youngjae Park & Sungsu Lim & Seulgi Shin & Srinivasrao Ganipisetti & Woo Seung Yang & Chang An Jung & Kun Young Kim & Eun Hye Jeong & S, 2022. "The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Harim I. Won & Samuel Zinga & Olga Kandror & Tatos Akopian & Ian D. Wolf & Jessica T. P. Schweber & Ernst W. Schmid & Michael C. Chao & Maya Waldor & Eric J. Rubin & Junhao Zhu, 2024. "Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Gang Xue & Jianing Xie & Matthias Hinterndorfer & Marko Cigler & Lara Dötsch & Hana Imrichova & Philipp Lampe & Xiufen Cheng & Soheila Rezaei Adariani & Georg E. Winter & Herbert Waldmann, 2023. "Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Meng, Zhaohui & Zheng, Haimin & Qin, Fankai & Li, Anqi & Li, Huimin & Dong, Sijie & Song, Chao & Miao, Xinyang & Yue, Wenzheng & Zhao, Kun & Zhan, Honglei, 2023. "Mechanistic study of the effect of hydrocarbon unsaturation on the distribution state of water molecules at the oil-water interface by oblique incident reflectance difference technique," Energy, Elsevier, vol. 276(C).

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