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Nature. 2019 Nov;575(7781):203-209. doi: 10.1038/s41586-019-1722-1. Epub 2019 Oct 30.

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

Author information

1
Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, School of Life Sciences, Fudan University, Shanghai, China.
2
Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai, China.
3
Large-scale Preparation System, National Facility for Protein Science in Shanghai, Shanghai, China.
4
Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China.
5
Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
6
Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Plymouth, UK.
7
Laboratory of Cellular Neurobiology, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
8
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
9
Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, School of Life Sciences, Fudan University, Shanghai, China. yuding@fudan.edu.cn.
10
Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai, China. fyy@fudan.edu.cn.
11
Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, School of Life Sciences, Fudan University, Shanghai, China. luboxun@fudan.edu.cn.

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.

PMID:
31666698
DOI:
10.1038/s41586-019-1722-1

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