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

  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},
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… 

ATTEC: a potential new approach to target proteinopathies

This study provides the initial validation of lowering mHTT by ATTEC, providing entry points to new treatment strategies of HD and similar diseases.

Discovery of an autophagy inducer J3 to lower mutant huntingtin and alleviate Huntington’s disease-related phenotype

In vivo studies revealed that J3 decreased T-HTT and misfolded protein levels in the striatum and increased the levels of the medium spiny neuron marker DARPP-32, suggesting that J 3 was a promising candidate for the treatment of HD.

Molecular Strategies to Target Protein Aggregation in Huntington’s Disease

Molecular strategies targeting mHTT and aggregates for degradation via the ubiquitin proteasome or the autophagy-lysosomal systems provide a knowledge-based approach to target HD and other neurodegenerative diseases at the origin.

Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin

The mechanism underlying mHtt degradation by the ubiquitin–proteasome system (UPS) is described, which has been shown to play a more important role than the autophagy–lysosomal pathway.

Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1

22 mutant ATXN1 regulators are identified by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes and among them, transglutaminase 5 (TG5) preferentially regulated mutant ATxN1 over the WT protein.

TBK1 regulates autophagic clearance of soluble mutant huntingtin and inhibits aggregation/toxicity in different models of Huntington’s disease

It is shown that overexpression of TBK1 in mammalian cells, primary neurons and a Caenorhabditis elegans model of Huntington’s Disease (HD) increases mutant HTTex1 phosphorylation, lowers its levels, increases its nuclear localization and significantly reduces its aggregation and cytotoxicity.

Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide

  • Haikun SongCen Wang B. Lu
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2022
Screen for compounds that directly bind to the undruggable target and rescue disease-relevant phenotypes via direct binding to it, and revealed desonide, an FDAapproved drug, as a possible lead compound for HD drug discovery.

Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties.

Conversion of protein degraders into hydrophobic tags (HyTs) could be a useful approach to improve their drug-like properties in neurodegenerative disorders.

Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases

The recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases is reviewed.



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.