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

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, Shouqing Luo, Yongjun Dang, Yu Ding (), Yiyan Fei () and Boxun Lu ()
Additional contact information
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

Nature, 2019, vol. 575, issue 7781, 203-209

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1722-1

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