Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex

Li, Xiaojing; Zhang, Yuanyuan; Fu, Yuhua; Zhang, Hao; Li, Hexuan; Li, Quan-Fu; Li, Hailing; Tan, Renke; Jiang, Chenxiao; Jiang, Wei; Li, Zeng-xia; Luo, Cheng; Lu, Boxun; Dang, Yongjun

doi:10.1038/s41401-020-00605-0

Cited by 11 publications

(8 citation statements)

References 46 publications

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“…GA also enhances the formation of the VCP–LC3–mHTT ternary complex by binding with VCP, leading to the degradation of mHTT in an autophagy-dependent manner at a concentration of 10 μM in iPS-derived Q47 neurons from Huntington’s disease (HD) patients. In both HD knock-in Drosophila and mouse models, GA ameliorated relevant motor function deficits . This study demonstrated the novel mechanism by which GA induces the degradation of mHTT in a gain-of-function manner, similar to the molecular glues rapamycin and FK506, and represented a novel strategy for the treatment of HD .…”

Section: Np-inspired Targeted Protein Degradersmentioning

confidence: 90%

“…In both HD knock-in Drosophila and mouse models, GA ameliorated relevant motor function deficits. 148 This study demonstrated the novel mechanism by which GA induces the degradation of mHTT in a gain-of-function manner, similar to the molecular glues rapamycin and FK506, and represented a novel strategy for the treatment of HD. 149 Further investigation of the mode of action between GA and the VCP−LC3−mHTT ternary complex is needed to concretely identify the molecular glue mechanism.…”

Section: Pseudolaric Acid Bmentioning

confidence: 99%

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Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Cai

et al. 2022

J. Med. Chem.

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Targeted protein degradation (TPD), a promising therapeutic strategy in drug discovery, has great potential to regulate the endogenous degradation of undruggable targets with small molecules. As vital resources that provide diverse structural templates for drug discovery, natural products (NPs) are a rising and robust arsenal for the development of therapeutic TPD. The first proof-of-concept study of proteolysis-targeting chimeras (PROTACs) was a natural polyketide ovalicin-derived degrader; since then, NPs have shown great potential to promote TPD technology. The use of NP-inspired targeted protein degraders has been confirmed to be a promising strategy to treat many human conditions, including cancer, inflammation, and nonalcoholic fatty liver disease. Nevertheless, the development of NP-inspired degraders is challenging, and the field is currently in its infancy. In this review, we summarize the bioactivities and mechanisms of NP-inspired degraders and discuss the associated challenges and future opportunities in this field.

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Section: Np-inspired Targeted Protein Degradersmentioning

confidence: 90%

Section: Pseudolaric Acid Bmentioning

confidence: 99%

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Cai

et al. 2022

J. Med. Chem.

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“…HD is a hereditary neurodegenerative disorder with expansion of CAG repeats in huntingtin (Htt) [80,81]. CAG causes the degeneration of the GABAergic projection neurons in the striatum regions and the development of involuntary movement and psychiatric disturbance [80][81][82][83]. There is no effective of treatment for HD.…”

Section: Huntington's Diseasementioning

confidence: 99%

“…Zhang et al [79] were among the early authors to generate an iPSCderived HD model. They developed iPSCs from HD patients displaying CAG repeats and then generated striatal neurons susceptible to cellular damage with typical characteristics of HD, such as mHTT aggregation and decreased concentrations of glutamate transporters and BDNF [80][81][82][83][84]. Their results showed an increased caspase activity upon growth factor deprivation, demonstrating the suitability of the HD iPSC-derived neurons for drug screening.…”

Section: Huntington's Diseasementioning

confidence: 99%

An insight into the iPSCs-derived two-dimensional culture and three-dimensional organoid models for neurodegenerative disorders

et al. 2022

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The use of induced pluripotent stem cells (iPSCs) is a promising approach when used as models to study neurodegenerative disorders (NDDs) in vitro . iPSCs have been used in in vitro two-dimensional cultures; however, these two-dimensional cultures do not mimic the physiological three-dimensional cellular environment. The use of iPSCs-derived three-dimensional organoids has risen as a powerful alternative to using animal models to study NDDs. These iPSCs-derived three-dimensional organoids can resemble the complexity of the tissue of interest, making it an approachable, cost-effective technique, to study NDDs in an ethical manner. Furthermore, the use of iPSCs-derived organoids will be an important tool to develop new therapeutics and pharmaceutics to treat NDDs. Herein, we will highlight how iPSCs-derived two-dimensional cultures and three-dimensional organoids have been used to study NDDs, as well as the advantages and disadvantages of both techniques.

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“…It was demonstrated in several models of HD that VCP selectively translocates to mitochondria where it binds mutant huntingtin, causing excessive mitophagy and neuronal death [ 98 ]. Modulating VCP-mutant huntingtin interaction with small molecule therapeutics has protective effects in HD mouse- and patient-derived cells and HD transgenic mouse brains [ 98 , 99 , 100 ].…”

Section: Mams In Neurodegenerative Diseasesmentioning

confidence: 99%

Connection Lost, MAM: Errors in ER–Mitochondria Connections in Neurodegenerative Diseases

Johri

Chandra

2021

Brain Sciences

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Mitochondria associated membranes (MAMs), as the name suggests, are the membranes that physically and biochemically connect mitochondria with endoplasmic reticulum. MAMs not only structurally but also functionally connect these two important organelles within the cell which were previously thought to exist independently. There are multiple points of communication between ER–mitochondria and MAMs play an important role in both ER and mitochondria functions such as Ca2+ homeostasis, proteostasis, mitochondrial bioenergetics, movement, and mitophagy. The number of disease-related proteins and genes being associated with MAMs has been continually on the rise since its discovery. There is an overwhelming overlap between the biochemical functions of MAMs and processes affected in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Thus, MAMs have received well-deserving and much delayed attention as modulators for ER–mitochondria communication and function. This review briefly discusses the recent progress made in this now fast developing field full of promise for very exciting future therapeutic discoveries.

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Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex

Cited by 11 publications

References 46 publications

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

An insight into the iPSCs-derived two-dimensional culture and three-dimensional organoid models for neurodegenerative disorders

Connection Lost, MAM: Errors in ER–Mitochondria Connections in Neurodegenerative Diseases

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