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

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

Publication date: Oct 30, 2019

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) 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 disorder. 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 tract. 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.

Li, Z., Wang, C., Wang, Z., Zhu, C., Li, J., Sha, T., Ma, L., Gao, C., Yang, Y., Sun, Y., Wang, J., Sun, X., Lu, C., Difiglia, M., Mei, Y., Ding, C., Luo, S., Dang, Y., Ding, Y., Fei, Y., and Lu, B. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. 06744. 2019 Nature.

Concepts Keywords
Allele Wild type
Autophagic Autophagosome
Huntingtin Autophagy
Huntington PolyQ
Interact Neurodegeneration
Linker Huntingtin
Microarray Trinucleotide repeat disorder
Microtubule Polyglutamine tract
Mutant Branches of biology
Nature Mutation
Neurodegenerative Disorder Mutant major diseases
Phenotypes ATXN3 disease
PolyQ Treatment diseases
Protein DNA Chip
Proteopathies
Small Molecule
Tethering
Vivo
Wild Type

Semantics

Type Source Name
gene UNIPROT ATXN3
gene UNIPROT HTT
gene UNIPROT SLC6A4
gene UNIPROT MAP1A
gene UNIPROT TNFSF14
disease MESH neurodegenerative disorder

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