RT Journal Article
SR Electronic
T1 The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.18.481043
DO 10.1101/2022.02.18.481043
A1 Itika Saha
A1 Patricia Yuste-Checa
A1 Miguel Da Silva Padilha
A1 Qiang Guo
A1 Roman Körner
A1 Hauke Holthusen
A1 Victoria A. Trinkaus
A1 Irina Dudanova
A1 Rubén Fernández-Busnadiego
A1 Wolfgang Baumeister
A1 David W. Sanders
A1 Saurabh Gautam
A1 Marc I. Diamond
A1 F. Ulrich Hartl
A1 Mark S. Hipp
YR 2022
UL http://biorxiv.org/content/early/2022/02/19/2022.02.18.481043.abstract
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 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.