Neuronal VCP loss of function recapitulates FTLD-TDP pathology

Abubakar Wani, Jiang Zhu, Jason D. Ulrich, Abdallah Eteleeb, Andrew D. Sauerbeck, Sydney J. Reitz, Khalid Arhzaouy, Chiseko Ikenaga, Carla M. Yuede, Sara K. Pittman, Feng Wang, Shan Li, Bruno A. Benitez, Carlos Cruchaga, Terrance T. Kummer, Oscar Harari, Tsui Fen Chou, Rolf Schröder, Christoph S. Clemen, Conrad C. Weihl

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.

Original languageEnglish
Article number109399
JournalCell Reports
Volume36
Issue number3
DOIs
StatePublished - Jul 20 2021

Keywords

  • FTD
  • FTLD
  • TDP-43
  • VCP
  • autophagy
  • multisystem proteinopathy
  • neurodegeneration
  • progranulin

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