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Wani A, Zhu J, Ulrich JD, et al. Neuronal VCP loss of function recapitulates FTLD-TDP pathology. Cell Rep. 2021;36(3):109399doi: 10.1016/j.celrep.2021.109399.
Wani, A., Zhu, J., Ulrich, J. D., Eteleeb, A., Sauerbeck, A. D., Reitz, S. J., Arhzaouy, K., Ikenaga, C., Yuede, C. M., Pittman, S. K., Wang, F., Li, S., Benitez, B. A., Cruchaga, C., Kummer, T. T., Harari, O., Chou, T. F., Schröder, R., Clemen, C. S., Weihl, C. C., & McLean, R. (2021). Neuronal VCP loss of function recapitulates FTLD-TDP pathology. Cell reports, 36(3), 109399. https://doi.org/10.1016/j.celrep.2021.109399
Wani, Abubakar, et al. "Neuronal VCP loss of function recapitulates FTLD-TDP pathology." Cell reports vol. 36,3 (2021): 109399. doi: https://doi.org/10.1016/j.celrep.2021.109399
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 TF, Schröder R, Clemen CS, Weihl CC, McLean R. Neuronal VCP loss of function recapitulates FTLD-TDP pathology. Cell Rep. 2021 Jul 20;36(3):109399. doi: 10.1016/j.celrep.2021.109399. PMID: 34289347; PMCID: PMC8383344.
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Cell Rep. 2021 Jul 20;36(3):109399. doi: 10.1016/j.celrep.2021.109399.

Neuronal VCP loss of function recapitulates FTLD-TDP pathology.

Cell reports

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, McLean

Affiliations

  1. Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA.
  2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  3. Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  4. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  5. Institute of Neuropathology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany.
  6. Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany; Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany.
  7. Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].

PMID: 34289347 PMCID: PMC8383344 DOI: 10.1016/j.celrep.2021.109399

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.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: FTD; FTLD; TDP-43; VCP; autophagy; multisystem proteinopathy; neurodegeneration; progranulin

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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