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Neuronal VCP loss of function recapitulates FTLD-TDP pathology

Wani, Abubakar and Zhu, Jiang and Ulrich, Jason D. and Eteleeb, Abdallah and Sauerbeck, Andrew D. and Reitz, Sydney J. and Arhzaouy, Khalid and Ikenaga, Chiseko and Yuede, Carla M. and Pittman, Sara K. and Wang, Feng and Li, Shan and Benitez, Bruno A. and Cruchaga, Carlos and Kummer, Terrance T. and Harari, Oscar and Chou, Tsui-Fen and Schröder, Rolf and Clemen, Christoph S. and Weihl, Conrad C. (2021) Neuronal VCP loss of function recapitulates FTLD-TDP pathology. Cell Reports, 36 (3). Art. No. 109399. ISSN 2211-1247. PMCID PMC8383344. doi:10.1016/j.celrep.2021.109399.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Wani, Abubakar0000-0001-7079-3278
Ulrich, Jason D.0000-0002-4743-926X
Ikenaga, Chiseko0000-0003-2264-1696
Yuede, Carla M.0000-0001-6362-4767
Li, Shan0000-0002-0829-1821
Benitez, Bruno A.0000-0002-2699-3878
Cruchaga, Carlos0000-0002-0276-2899
Kummer, Terrance T.0000-0001-8938-8280
Harari, Oscar0000-0002-2635-6975
Chou, Tsui-Fen0000-0003-2410-2186
Schröder, Rolf0000-0002-2772-2615
Clemen, Christoph S.0000-0002-1291-4219
Weihl, Conrad C.0000-0002-3816-6124
Additional Information:© 2021 The Author(s). This is an open access article under the CC BY-NC-ND license ( Received 4 January 2021, Revised 6 April 2021, Accepted 22 June 2021, Available online 21 July 2021. This work was supported by NIH grants K24AR073317 and R01AG031867 (to C.C.W.); I01BX005204 to (T.T.K.); R01AG044546, P01AG003991, P30AG066444, RF1AG053303, RF1AG058501, and U01AG058922 (to C.C.); R01AG057777 (to O.H.); R01NS118146 (to B.A.B.); and R01NS102279 (to T.F.C. and C.C.W.). O.H. is supported as an Archer Foundation Research Scientist. Author contributions: A.W., J.Z., J.D.U., A.E., A.D.S., S.J.R., K.A., S.K.P., F.W., S.L., and B.A.B. performed experiments. A.W., J.Z., J.D.U., A.E., A.D.S., C.I., C.M.Y., C.C., T.T.K., O.H., T.-F.C., R.S., C.S.C., and C.C.W. analyzed data. C.C.W. and O.H. guided experiments. C.C.W. and A.W. wrote the initial manuscript and edited subsequent versions of the manuscript. O.H., J.D.U., T.T.K., and T.-F.C. wrote critical sections of the manuscript. C.C.W. edited and wrote the final version of the manuscript. All authors reviewed and edited the final version of the manuscript. C.C.W. conceived the project and directed all experiments. The authors declare no competing interests.
Funding AgencyGrant Number
Archer FoundationUNSPECIFIED
Issue or Number:3
PubMed Central ID:PMC8383344
Record Number:CaltechAUTHORS:20210811-212815828
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Official Citation: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, Neuronal VCP loss of function recapitulates FTLD-TDP pathology, Cell Reports, Volume 36, Issue 3, 2021, 109399, ISSN 2211-1247, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110204
Deposited By: Tony Diaz
Deposited On:11 Aug 2021 21:54
Last Modified:26 Aug 2021 16:37

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