ArticleThe Journal of clinical investigation2024
VCP activator reverses nuclear proteostasis defects and enhances TDP-43 aggregate clearance in multisystem proteinopathy models.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.The EMBO journal · 2026Article
- Stimulating proteasomal degradation in human proteinopathies.The FEBS journal · 2026Review
- A Pyrazole-Based Small Molecule, KB3409, Restores Mitochondrial Function via VCP Activation and RCN2-Dependent CaAntioxidants (Basel, Switzerland) · 2026Article
- Valosin-containing protein is cargo in Amyloid Precursor Protein extracellular vesicles.Cell communication and signaling : CCS · 2026Article
- ASPL-driven subunit exchange remodels VCP/p97 hexamers and is impaired by a multisystem proteinopathy mutation.bioRxiv : the preprint server for biology · 2026Article
- Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.BMB reports · 2026Review
- The VCPKMT-VCP-HDAC1 axis inhibits colorectal cancer by conferring sensitivity to ferroptosis.Cancer cell international · 2025Article
- Clinicopathological characterization of vacuolar tauopathy associated with VCP D395G.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Validity and Reliability of Clinical and Patient-Reported Outcomes in Multisystem Proteinopathy 1.Annals of clinical and translational neurology · 2025Article
- Structural insights into the coupling between VCP, an essential unfoldase, and a deubiquitinase.The Journal of cell biology · 2025Article
- 2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy.Neurobiology of disease · 2025Review
- VCP regulates early tau seed amplification via specific cofactors.Molecular neurodegeneration · 2025Article
- Design principles to tailor Hsp104 therapeutics.Cell reports · 2024Article
- Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics.Cell · 2024Article
- Fatty links between multisystem proteinopathy and small VCP-interacting protein.Cell death discovery · 2024Article
- Allosteric activation of VCP, an AAA unfoldase, by small molecule mimicry.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- VCP regulates early tau seed amplification via specific cofactors.Research square · 2024Article
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Abstract
Pathogenic variants in valosin-containing protein (VCP) cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature: ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts, and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified 4 compounds that activate VCP primarily by increasing D2 ATPase activity, where pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that impaired nuclear proteostasis may contribute to MSP, and that VCP activation may be a potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.