| First Author | Wani A | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 3 | Pages | 109399 |
| PubMed ID | 34289347 | Mgi Jnum | J:324879 |
| Mgi Id | MGI:6876829 | Doi | 10.1016/j.celrep.2021.109399 |
| Citation | Wani A, et al. (2021) Neuronal VCP loss of function recapitulates FTLD-TDP pathology. Cell Rep 36(3):109399 |
| abstractText | 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. |
