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

Saha, Itika; Yuste-Checa, Patricia; Padilha, Miguel Da Silva; Guo, Qiang; Koerner, Roman; Holthusen, Hauke; Trinkaus, Victoria A.; Dudanova, Irina; Fernandez-Busnadiego, Ruben; Baumeister, Wolfgang; Sanders, David W.; Gautam, Saurabh; Diamond, Marc I.; Hartl, F. Ulrich und Hipp, Mark S. (2023): The AAA plus chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system. In: Nature Communications, Bd. 14, Nr. 1, 560

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198