TY - JOUR T1 - The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds JF - bioRxiv DO - 10.1101/2022.02.18.481043 SP - 2022.02.18.481043 AU - Itika Saha AU - Patricia Yuste-Checa AU - Miguel Da Silva Padilha AU - Qiang Guo AU - Roman Körner AU - Hauke Holthusen AU - Victoria A. Trinkaus AU - Irina Dudanova AU - Rubén Fernández-Busnadiego AU - Wolfgang Baumeister AU - David W. Sanders AU - Saurabh Gautam AU - Marc I. Diamond AU - F. Ulrich Hartl AU - Mark S. Hipp Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/02/19/2022.02.18.481043.abstract N2 - 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 AAA+ chaperone VCP is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with Hsp70 and the ubiquitin-proteasome machinery. Inhibition of VCP activity stabilizes large Tau aggregates, and is accompanied by a reduction in the amount of Tau species competent of prion- like aggregate seeding in recipient cells. Thus, disaggregation by VCP generates seeding-active Tau 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.Competing Interest StatementThe authors have declared no competing interest. ER -