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

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

doi:10.1038/s41467-023-36058-2

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

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Saha, Itika
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons248333

Yuste-Checa, Patricia
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons216754

Guo, Qiang
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78244

Körner, Roman
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons216614

Holthusen, Hauke
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons261161

Trinkaus, Victoria A.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons77952

Fernandez-Busnadiego, Ruben
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons77721

Baumeister, Wolfgang
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons294058

Gautam, Saurabh
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78072

Hartl, F. Ulrich
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78111

Hipp, Mark S.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Saha, I., Yuste-Checa, P., Padilha, M. D. S., Guo, Q., Körner, R., Holthusen, H., et al. (2023). The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system. Nature Communications, 14(1): 560. doi:10.1038/s41467-023-36058-2.

Cite as: https://hdl.handle.net/21.11116/0000-000E-0050-7

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 inmammalian 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.