GSE178257
Neuronal VCP loss of function recapitulates FTLD-TDP pathology
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 inactivated VCP in murine postnatal forebrain neurons (VCP 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 recapitulated 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. Overall design: Droplet-based 3' end massively parallel single-cell RNA sequencing was performed by isolating single nuclei from flash-frozen mouse brains through sucrose gradient and libraries were prepared using Chromium Single Cell 5' Reagent Kits according to manufacturer's protocol (10x Genomics). The generated scRNAseq libraries were sequenced using Illumina sequencers.