Neuronal VCP loss of function recapitulates FTLD-TDP pathology
- Creators
- Wani, Abubakar
- Zhu, Jiang
- Ulrich, Jason D.
- Eteleeb, Abdallah
- Sauerbeck, Andrew D.
- Reitz, Sydney J.
- Arhzaouy, Khalid
- Ikenaga, Chiseko
- Yuede, Carla M.
- Pittman, Sara K.
- Wang, Feng
- Li, Shan
- Benitez, Bruno A.
- Cruchaga, Carlos
- Kummer, Terrance T.
- Harari, Oscar
- Chou, Tsui-Fen
- Schröder, Rolf
- Clemen, Christoph S.
- Weihl, Conrad C.
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.
Additional Information
© 2021 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 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.Attached Files
Published - 1-s2.0-S221112472100797X-main.pdf
Supplemental Material - 1-s2.0-S221112472100797X-mmc1.pdf
Supplemental Material - 1-s2.0-S221112472100797X-mmc2.xlsx
Supplemental Material - 1-s2.0-S221112472100797X-mmc3.xlsx
Supplemental Material - 1-s2.0-S221112472100797X-mmc4.xlsx
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Additional details
- PMCID
- PMC8383344
- Eprint ID
- 110204
- Resolver ID
- CaltechAUTHORS:20210811-212815828
- K24AR073317
- NIH
- R01AG031867
- NIH
- I01BX005204
- NIH
- R01AG044546
- NIH
- P01AG003991
- NIH
- P30AG066444
- NIH
- RF1AG053303
- NIH
- RF1AG058501
- NIH
- U01AG058922
- NIH
- R01AG057777
- NIH
- R01NS118146
- NIH
- R01NS102279
- NIH
- Archer Foundation
- Created
-
2021-08-11Created from EPrint's datestamp field
- Updated
-
2021-08-26Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering