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

@article{Li2019AlleleselectiveLO,
  title={Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds},
  author={Zhaoyang Li and Cen Wang and Ziying Wang and Cheng-long Zhu and Jie Li and Tianle Sha and Lixiang Ma and Chao Gao and Yi Yang and Yi-Min Sun and Jian Wang and Xiaoli Sun and Chenqi Lu and Marian DiFiglia and Yanai Mei and Chen Ding and Shouqing Luo and Yongjun Dang and Yu Ding and Yiyan Fei and Boxun Lu},
  journal={Nature},
  year={2019},
  volume={575},
  pages={203-209}
}
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… 

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  • Haikun SongCen Wang B. Lu
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2022
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References

SHOWING 1-10 OF 42 REFERENCES

Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells.

These phenotypes indicate a disruption of striatal cell homeostasis by the mutant protein, via a mechanism that is separate from its normal activity, and support specific stress pathways, including elevated p53, endoplasmic reticulum stress response and hypoxia, as potential players in HD.

Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis

It is found that loss of Htt causes the lethal phenotype only in postnatal mice but not in adult mice, and this early death is due to acute pancreatitis, indicating the safety in knocking down neuronal HTT in adult brains for treating Huntington’s disease.

Catalytic in vivo protein knockdown by small-molecule PROTACs.

Major improvements to the proteolysis targeting chimeras (PROTACs) method are described, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation.

Identifying polyglutamine protein species in situ that best predict neurodegeneration

The results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.

Huntingtin’s spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function

It is shown that the polyglutamine expansion increases α-helical properties of huntingtin and affects the intramolecular interactions among the domains, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglUTamine tract confers a novel property on huntingtin, causing Huntington’s disease.