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Novel VCP activator reverses multisystem proteinopathy nuclear proteostasis defects and enhances TDP-43 aggregate clearance.

ABSTRACT: Pathogenic variants in 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 four novel compounds that activate VCP primarily by increasing D2 ATPase activity whereby 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 MSP may be the result of impaired nuclear proteostasis, and that VCP activation may be potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.

SUBMITTER: Phan JM

PROVIDER: S-EPMC10055171 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Novel VCP activator reverses multisystem proteinopathy nuclear proteostasis defects and enhances TDP-43 aggregate clearance.

Phan Jessica M JM Creekmore Benjamin C BC Nguyen Aivi T AT Bershadskaya Darya D DD Darwich Nabil F NF Lee Edward B EB

bioRxiv : the preprint server for biology 20230315

Pathogenic variants in <i>VCP</i> 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 ...[more]

PMID: 36993559

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Project description:BackgroundValosin containing protein (VCP) is an important protein with many vital functions mostly related to the ubiquitin-proteasome system that provides protein quality control. VCP-associated inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also termed VCP disease and multisystem proteinopathy (MSP 1), is an autosomal dominant disorder caused by monoallelic variants in the VCP gene on human chromosome 9. VCP has also been strongly involved in cancer, with over-activity of VCP found in several cancers such as prostate, pancreatic, endometrial, esophageal cancers and osteosarcoma. Since MSP1 is caused by gain of function variants in the VCP gene, we hypothesized our patients would show increased risk for developing malignancies. We describe cases of 3 rare malignancies and 4 common cancers from a retrospective dataset.ResultsUpon surveying 106 families with confirmed VCP variants, we found a higher rate of rare tumors including malignant peripheral nerve sheath tumor, anaplastic pleomorphic xanthoastrocytoma and thymoma. Some of these subjects developed cancer before displaying other classic VCP disease manifestations. We also present cases of common cancers; however, we did not find an increased rate compared to the general population. This could be related to the early mortality associated with this disease, since most patients die in their 50-60 s due to respiratory failure or cardiomyopathy which is earlier than the age at which most cancers appear.ConclusionThis is the first study that expands the phenotype of VCP disease to potentially include rare cancers and highlights the importance of further investigation of the role of VCP in cancer development. The results of this study in VCP disease patients suggest that patients may be at an increased risk for rare tumors. A larger study will determine if patients with VCP disease develop cancer at a higher rate than the general population. If that is the case, they should be followed up more frequently and screened for recurrence and metastasis of their cancer.

Dataset Information

Novel VCP activator reverses multisystem proteinopathy nuclear proteostasis defects and enhances TDP-43 aggregate clearance.

Publications

Novel VCP activator reverses multisystem proteinopathy nuclear proteostasis defects and enhances TDP-43 aggregate clearance.

Similar Datasets

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