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

• Published in: Nature communications Vol. 14; no. 1; p. 560
• Main Authors: Saha, Itika, Yuste-Checa, Patricia, Da Silva Padilha, Miguel, Guo, Qiang, Körner, Roman, Holthusen, Hauke, Trinkaus, Victoria A., Dudanova, Irina, Fernández-Busnadiego, Rubén, Baumeister, Wolfgang, Sanders, David W., Gautam, Saurabh, Diamond, Marc I., Hartl, F. Ulrich, Hipp, Mark S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-02-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 13/31; 14/1; 14/19; 14/28; 14/33; 14/35; 14/63; 45/29; 631/45/474/1768; 631/45/612/1981; 631/80/470/2284; 64/110; 82/58; Aggregates; Alzheimer Disease; Alzheimer's disease; Amyloid; Animals; Byproducts; Cell culture; Cooperativity; Disaggregation; Fibrils; Heat shock; Heat shock proteins; Heat-Shock Proteins - metabolism; Hsp70 protein; Humanities and Social Sciences; Humans; Mammalian cells; Mammals - metabolism; Molecular Chaperones - metabolism; multidisciplinary; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Proteasomes; Protein seeding; Proteins; Science; Science (multidisciplinary); Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Ubiquitin; Valosin Containing Protein - genetics; Valosin Containing Protein - metabolism; Valosin-containing protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36058-2

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.
Tau aggregates are associated with several neurodegenerative disorders. In this work, I. Saha and colleagues show that valosin-containing protein (VCP) recruited to Tau fibrils disaggregates them. However, this process comes at a cost: it generates seeding-active Tau species as byproduct.