Neuronal VCP loss of function recapitulates FTLD-TDP pathology

Author(s): Wani, A; Zhu, J; Ulrich, JD; Eteleeb, A; Sauerbeck, AD; Reitz, SJ; Arhzaouy, K; Ikenaga, C; Yuede, CM; Pittman, SK; Wang, F; Li, S; Benitez, BA; Cruchaga, C; Kummer, TT; Harari, O; Chou, T; Schröder, R; Clemen, CS; Weihl, CC;
Year: 2021;  
Journal: Cell Reports;  
Volume: 36;  
Issue: 3;  

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.