Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds
View/ Open
Date
2019-10-30Author
Subject
Metadata
Show full item recordAbstract
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.
Collections
Publisher
Place of Publication
Journal
Volume
Issue
Pagination
Recommended, similar items
The following license files are associated with this item:
Related items
Showing items related by title, author, creator and subject.
-
Cytoplasmic DAXX drives SQSTM1/p62 phase condensation to activate Nrf2-mediated stress response
Yang, Y; Willis, TL; Button, RW; Strang, CJ; Fu, Y; Wen, X; Grayson, PRC; Evans, T; Sipthorpe, RJ; Roberts, SL; Hu, Bing; Zhang, J; Lu, B; Luo, Shouqing (Springer Science and Business Media LLCEngland, 2019-08-21)<jats:title>Abstract</jats:title><jats:p>Autophagy cargo recognition and clearance are essential for intracellular protein quality control. SQSTM1/p62 sequesters intracellular aberrant proteins and mediates cargo delivery ... -
Molecular basis for Jagged-1/Serrate ligand recognition by the Notch receptor.
Whiteman, P; de Madrid, BH; Taylor, P; Li, D; Heslop, R; Viticheep, N; Tan, JZ; Shimizu, H; Callaghan, J; Masiero, M; Li, JL; Banham, AH; Harris, AL; Lea, SM; Redfield, C; Baron, M; Handford, PA (United States, 2013-03-08)We have mapped a Jagged/Serrate-binding site to specific residues within the 12th EGF domain of human and Drosophila Notch. Two critical residues, involved in a hydrophobic interaction, provide a ligand-binding platform ... -
Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function.
Williams, CK; Li, J-L; Murga, M; Harris, AL; Tosato, G (United States, 2006-02-01)Delta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing endothelium and in some tumor endothelium, and it is induced by vascular endothelial growth factor (VEGF)-A ...