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Loss-of-function mutation in VCP mimics the characteristic pathology as in FTLD-TARDBP
Abubakar Wani1,2, Conrad C Weihl1
1Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
VCP (valosin containing protein), a member of the AAA+ protein family, is critical for many cellular processes and functions. Dominant VCP mutations cause a rare neurodegenerative disease known as multisystem proteinopathy (MSP). The spectrum of mechanisms causing fronto-temporal dementia with TARDBP/TDP-43 inclusions (FTLD-TARDBP) by VCP disease mutations remains unclear. Our recent work identified VCP activity as a mediator of FTLD-TARDBP. Specifically, brain atrophy, behavioral changes, neuronal loss, gliosis, and TARDBP pathology were observed in vcp conditional knockout (cKO) mice. We also found that autophago-lysosomal dysfunction, TARDBP inclusions, and ubiquitin-proteasome impairment precede neuronal loss. We further studied conditional expression of the disease-associated mutation VCPR155C in vcp-null mice. We observed features similar to those of VCP inactivation, suggesting that VCP mutation is hypomorphic. Furthermore, proteomic, and transcriptomic signatures in vcp cKO mice resemble those of GRN/Progranulin carriers. Therefore, VCP is essential for neuronal survival by several mechanisms and could be a therapeutic target aimed at restoring protein homeostasis in patients with FTLD-TARDBP.
Insights
Valosin-containing protein (VCP) mutations cause neurodegenerative multisystem proteinopathy (MSP). VCP dysfunction impairs protein clearance and neuronal survival, offering a therapeutic target for frontotemporal dementia.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Valosin-containing protein (VCP) is vital for cellular functions and its mutations cause multisystem proteinopathy (MSP).
- The precise mechanisms linking VCP mutations to frontotemporal dementia with TARDBP/TDP-43 inclusions (FTLD-TARDBP) are not fully understood.
Purpose of the Study:
- To investigate the role of VCP in FTLD-TARDBP pathogenesis.
- To explore VCP's impact on neuronal survival and protein homeostasis.
Main Methods:
- Utilized VCP conditional knockout (cKO) mouse models.
- Analyzed brain pathology, including atrophy, neuronal loss, gliosis, and TARDBP inclusions.
- Assessed autophagosome-lysosome and ubiquitin-proteasome system function.
- Investigated the VCP R155C mutation's effects and performed proteomic/transcriptomic analyses.
Main Results:
- VCP deficiency in mice recapitulated key features of FTLD-TARDBP, including brain atrophy and TARDBP pathology.
- Autophagosome-lysosome and ubiquitin-proteasome dysfunction preceded neuronal death.
- The VCP R155C mutation exhibited hypomorphic activity, similar to VCP inactivation.
- Molecular signatures in VCP cKO mice mirrored those of GRN/Progranulin mutation carriers.
Conclusions:
- VCP is crucial for neuronal survival through multiple mechanisms, including maintaining protein homeostasis.
- VCP dysfunction, whether through mutation or inactivation, contributes significantly to FTLD-TARDBP.
- Restoring VCP function presents a potential therapeutic strategy for FTLD-TARDBP.
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