Journal Article

VCP activator reverses nuclear proteostasis defects and enhances TDP-43 aggregate clearance in multisystem proteinopathy models

Creekmore, Benjamin C., Mann, Carolyn N., Bershadskaya, Darya D., Darwich, Nabil F., Lee, Edward B., Phan, Jessica M., Nguyen, Aivi T.

2024

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adenosine triphosphatase / Analysis / Animals / Cell Nucleus - metabolism / Computer industry / Dementia / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Frontotemporal Dementia - drug therapy / Frontotemporal Dementia - genetics / Frontotemporal Dementia - metabolism / Frontotemporal Dementia - pathology / Humans / Intranuclear Inclusion Bodies - genetics / Intranuclear Inclusion Bodies - metabolism / Intranuclear Inclusion Bodies - pathology / Mice / Myositis, Inclusion Body - drug therapy / Myositis, Inclusion Body - genetics / Myositis, Inclusion Body - metabolism / Myositis, Inclusion Body - pathology / Neuroscience / Osteitis Deformans - drug therapy / Osteitis Deformans - genetics / Osteitis Deformans - metabolism / Osteitis Deformans - pathology / Protein Aggregates - drug effects / Proteostasis / Scientific equipment and supplies industry / TDP-43 Proteinopathies - drug therapy / TDP-43 Proteinopathies - genetics / TDP-43 Proteinopathies - metabolism / TDP-43 Proteinopathies - pathology / Therapeutics / Valosin Containing Protein - genetics / Valosin Containing Protein - metabolism