Neuronal VCP loss of function recapitulates FTLD-TDP pathology

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 (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Cell Reports Elsevier (Cell Press)

Book Volume: 36

Article Number: 109399

Journal Issue: 3

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.

Authors with CRIS profile

Rolf Schröder Professur für Neuropathologie

Involved external institutions

Washington University US United States (USA) (US) California Institute of Technology (Caltech) US United States (USA) (US) Deutsches Zentrum für Luft- und Raumfahrt e.V. (DLR) / German Aerospace Center DE Germany (DE)

How to cite

APA:

Wani, A., Zhu, J., Ulrich, J.D., Eteleeb, A., Sauerbeck, A.D., Reitz, S.J.,... Weihl, C.C. (2021). Neuronal VCP loss of function recapitulates FTLD-TDP pathology. Cell Reports, 36(3). https://doi.org/10.1016/j.celrep.2021.109399

MLA:

Wani, Abubakar, et al. "Neuronal VCP loss of function recapitulates FTLD-TDP pathology." Cell Reports 36.3 (2021).

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