Loss-of-function mutation in VCP mimics the characteristic pathology as in FTLD-TARDBP.

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.