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

Autophagy. 2021 Dec;17(12):4502-4503. doi: 10.1080/15548627.2021.1985880. Epub 2021 Oct 10.

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.

Keywords: Autophagy; FTLD-TDP-43; neurodegeneration; progranulin; valosin-containing protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy / genetics
  • DNA-Binding Proteins / metabolism
  • Frontotemporal Lobar Degeneration* / genetics
  • Frontotemporal Lobar Degeneration* / metabolism
  • Humans
  • Lysosomes / metabolism
  • Mice
  • Mutation / genetics
  • Neurodegenerative Diseases* / genetics
  • Neurodegenerative Diseases* / metabolism
  • Proteomics
  • Valosin Containing Protein* / genetics
  • Valosin Containing Protein* / metabolism

Substances

  • DNA-Binding Proteins
  • VCP protein, human
  • Valosin Containing Protein
  • Vcp protein, mouse