Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds
Open accessAbstract
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 disorder 2. 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 3. 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.
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In 2019, Lu et al. proposed a direct strategy for selective degradation of mHTT using ATTECs; small-molecule microarray-based screening identified four compounds (10O5, AN1, AN2, 8F20) that interacted with LC3 and mHTT, leading to degradation.
“In 2019, Lu et al. proposed a direct strategy for the selective degradation of mHTT using autophagosome-tethering compound (ATTECs). Small-molecule microarray-based screening identified four compounds (10O5 (227), AN1 (228), AN2 (229), and 8F20 (230)) that interacted with LC3 and mHTT, leading to degradation (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [539]
Two small-molecule TPD strategies have been reported to lower mHTT levels: a small-molecule glue approach inducing proximity between mHTT and MAP1LC3α to target it to autophagy for degradation; and small-molecule PROTACs that recruit mHTT aggregates to E3 ligases from the IAP family, causing proteasomal degradation of the mutant protein.
“In fact, two small-molecule TPD strategies have been reported to lower mHTT levels: a small-molecule glue approach inducing the proximity between mHTT and microtubule-associated protein 1 light chain 3α (MAP1LC3α; also known as LC3) to target it to the autophagy pathway for degradation196; and small-molecule PROTACs that recruit mHTT aggregates to E3 ligases from the IAP family, causing the protea”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [196]
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“Other bivalent degraders follow a similar logic: lysosome-targeting chimeras (lytAcs) engage lysosomal degradation pathways (Banik et al. 2020) whereas autophagy-targeting chime-ras (AutAcs) interact with autophagosomal components to initiate autophagy (li et al. 2019; takahashi et al. 2019).”
- Authors
- 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., & Lu, B.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- University of Plymouth (GB)
- Massachusetts General Hospital (US)
- Corresponding author
- Ding, Yu
- Fei, Yiyan
- Lu, Boxun
- ORCID
- Venue
- Nature
- Published
- 2019-10-30
- Volume
- 575
- Issue
- 7781
- Pages
- 203-209
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2982548291
- Cited by
- 551
- References
- 41
- Citations by year
- 2026: 82 · 2025: 100 · 2024: 82 · 2023: 75 · 2022: 96 · 2021: 67 · 2020: 40 · 2019: 7 · 2014: 1
- FWCI
- 25.32
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- PEARL (University of Plymouth) (submittedVersion, cc-by-nc)
- Funders
- Academy of Medical Sciences (NAF009\1001)
- Medical Research Council (MR/M023605/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- mutant huntingtin, Huntington's disease, polyglutamine expansion, LC3, autophagy, proteinopathies, ataxin-3, small molecule screening, neurodegenerative disease treatment
- MeSH terms
- Ataxin-3, Huntingtin Protein, Autophagosomes, Alleles, Animals, Autophagy, Disease Models, Animal, Drosophila melanogaster, Drug Evaluation, Preclinical, Female, Humans, Male, Microtubule-Associated Proteins, Mutation, Neurons, Peptides, Phenotype, Reproducibility of Results, Drosophila Proteins, Mutant Proteins, Mice
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