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

Itika Saha, Patricia Yuste-Checa, Miguel 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 () and Mark S. Hipp ()
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Itika Saha: Max Planck Institute of Biochemistry
Patricia Yuste-Checa: Max Planck Institute of Biochemistry
Miguel Silva Padilha: Max Planck Institute for Biological Intelligence
Qiang Guo: Max Planck Institute of Biochemistry
Roman Körner: Max Planck Institute of Biochemistry
Hauke Holthusen: Max Planck Institute of Biochemistry
Victoria A. Trinkaus: Max Planck Institute of Biochemistry
Irina Dudanova: Max Planck Institute for Biological Intelligence
Rubén Fernández-Busnadiego: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
Wolfgang Baumeister: Max Planck Institute of Biochemistry
David W. Sanders: University of Texas Southwestern Medical Center
Saurabh Gautam: Max Planck Institute of Biochemistry
Marc I. Diamond: University of Texas Southwestern Medical Center
F. Ulrich Hartl: Max Planck Institute of Biochemistry
Mark S. Hipp: Max Planck Institute of Biochemistry

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36058-2

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