Universität zu Köln

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 ORCID: 0000-0002-0276-2899, Kummer, Terrance T., Harari, Oscar, Chou, Tsui-Fen, Schroder, Rolf, Clemen, Christoph S. and Weihl, Conrad C. (2021). Neuronal VCP loss of function recapitulates FTLD-TDP pathology. Cell Reports, 36 (3). CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wani, Abubakar UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhu, Jiang UNSPECIFIED UNSPECIFIED UNSPECIFIED Ulrich, Jason D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Eteleeb, Abdallah UNSPECIFIED UNSPECIFIED UNSPECIFIED Sauerbeck, Andrew D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reitz, Sydney J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Arhzaouy, Khalid UNSPECIFIED UNSPECIFIED UNSPECIFIED Ikenaga, Chiseko UNSPECIFIED UNSPECIFIED UNSPECIFIED Yuede, Carla M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pittman, Sara K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Feng UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Shan UNSPECIFIED UNSPECIFIED UNSPECIFIED Benitez, Bruno A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cruchaga, Carlos UNSPECIFIED orcid.org/0000-0002-0276-2899 UNSPECIFIED Kummer, Terrance T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Harari, Oscar UNSPECIFIED UNSPECIFIED UNSPECIFIED Chou, Tsui-Fen UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroder, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Clemen, Christoph S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Weihl, Conrad C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-592607
DOI:	10.1016/j.celrep.2021.109399
Journal or Publication Title:	Cell Reports
Volume:	36
Number:	3
Date:	2021
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2211-1247
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VALOSIN-CONTAINING-PROTEIN; FRONTOTEMPORAL DEMENTIA; ONSET ALZHEIMERS; ATPASE ACTIVITY; PROGRANULIN; MUTATIONS; UBIQUITIN; MICE; MUSCLE; BRAIN Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59260