The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system

Itika Saha; Patricia Yuste-Checa; Miguel Da Silva Padilha; Qiang Guo; Roman Körner; Hauke Holthusen; Victoria A. Trinkaus; Irina Dudanova; Rubén Fernández-Busnadiego; Wolfgang Baumeister; David W. Sanders; Saurabh Gautam; Marc I. Diamond; F. Ulrich Hartl; Mark S. Hipp

doi:10.1038/s41467-023-36058-2

The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system

Itika Saha, Patricia Yuste-Checa, Miguel Da Silva Padilha, Qiang Guo, Roman Körner, Hauke Holthusen, Victoria A. Trinkaus, Irina Dudanova, Rubén Fernández-Busnadiego, Wolfgang Baumeister, David W. Sanders, Saurabh Gautam, Marc I. Diamond, F. Ulrich Hartl, Mark S. Hipp

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Abstract

Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer’s disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with heat shock 70 kDa protein (Hsp70) and the ubiquitin-proteasome machinery. While inhibition of VCP activity stabilizes large Tau aggregates, disaggregation by VCP generates seeding-active Tau species as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.

Original language	English (US)
Article number	560
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36058-2
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Saha, I., Yuste-Checa, P., Da Silva Padilha, M., Guo, Q., Körner, R., Holthusen, H., Trinkaus, V. A., Dudanova, I., Fernández-Busnadiego, R., Baumeister, W., Sanders, D. W., Gautam, S., Diamond, M. I., Hartl, F. U., & Hipp, M. S. (2023). The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system. Nature communications, 14(1), Article 560. https://doi.org/10.1038/s41467-023-36058-2

Saha, I, Yuste-Checa, P, Da Silva Padilha, M, Guo, Q, Körner, R, Holthusen, H, Trinkaus, VA, Dudanova, I, Fernández-Busnadiego, R, Baumeister, W, Sanders, DW, Gautam, S, Diamond, MI, Hartl, FU & Hipp, MS 2023, 'The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system', Nature communications, vol. 14, no. 1, 560. https://doi.org/10.1038/s41467-023-36058-2

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abstract = "Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer{\textquoteright}s disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with heat shock 70 kDa protein (Hsp70) and the ubiquitin-proteasome machinery. While inhibition of VCP activity stabilizes large Tau aggregates, disaggregation by VCP generates seeding-active Tau species as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.",

author = "Itika Saha and Patricia Yuste-Checa and {Da Silva Padilha}, Miguel and Qiang Guo and Roman K{\"o}rner and Hauke Holthusen and Trinkaus, {Victoria A.} and Irina Dudanova and Rub{\'e}n Fern{\'a}ndez-Busnadiego and Wolfgang Baumeister and Sanders, {David W.} and Saurabh Gautam and Diamond, {Marc I.} and Hartl, {F. Ulrich} and Hipp, {Mark S.}",

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AU - Körner, Roman

AU - Holthusen, Hauke

AU - Trinkaus, Victoria A.

AU - Dudanova, Irina

AU - Fernández-Busnadiego, Rubén

AU - Baumeister, Wolfgang

AU - Sanders, David W.

AU - Gautam, Saurabh

AU - Diamond, Marc I.

AU - Hartl, F. Ulrich

AU - Hipp, Mark S.

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AB - Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer’s disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with heat shock 70 kDa protein (Hsp70) and the ubiquitin-proteasome machinery. While inhibition of VCP activity stabilizes large Tau aggregates, disaggregation by VCP generates seeding-active Tau species as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.

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The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system

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