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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Valosin-containing protein (VCP) gene variants cause multisystem proteinopathy (MSP), a condition with diverse clinical presentations including myopathy, bone disease, and frontotemporal dementia.
• The underlying mechanisms linking VCP variants to these varied phenotypes remain unclear.
• A common pathological hallmark across MSP subtypes is the presence of ubiquitinated intranuclear inclusions in affected cells.

Purpose of the Study:

• To investigate the role of VCP in nuclear protein homeostasis.
• To understand how VCP dysfunction contributes to the pathogenesis of MSP.
• To identify potential therapeutic strategies for MSP by targeting VCP activity.

Main Methods:

• Analysis of cell lines with MSP-associated VCP variants.
• Development of a cellular model for intranuclear TDP-43 aggregate formation under proteostatic stress.
• Assessment of VCP inhibitor effects on TDP-43 aggregate clearance.
• Screening for compounds that activate VCP function.

Main Results:

• MSP-associated VCP variants lead to reduced nuclear VCP levels and impaired clearance of intranuclear TDP-43 aggregates.
• VCP inhibition exacerbates the accumulation of these aggregates.
• Four compounds were identified that activate VCP by enhancing its D2 ATPase activity.
• Pharmacological activation of VCP promotes the clearance of insoluble intranuclear TDP-43 aggregates.

Conclusions:

• VCP plays a critical role in maintaining nuclear protein homeostasis.
• Impaired nuclear proteostasis due to VCP dysfunction is implicated in MSP pathogenesis.
• VCP activation represents a promising therapeutic avenue for enhancing the clearance of intranuclear protein aggregates in MSP.