Skip to Content
Merck
  • The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system.

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

Nature communications (2023-02-03)
Itika Saha, Patricia Yuste-Checa, Miguel Da 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, Mark S Hipp
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-NPLOC4 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution, Ab1
Sigma-Aldrich
Anti-Rabbit IgG (whole molecule)–Peroxidase antibody produced in goat, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
Anti-Ubiquitinylated proteins Antibody, clone FK2, clone FK2, Upstate®, from mouse
Sigma-Aldrich
Anti-LC3B antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Ubiquitin Antibody, Lys63-Specific, clone Apu3, rabbit monoclonal, clone Apu3, from rabbit
Sigma-Aldrich
Anti-α-Tubulin antibody, Mouse monoclonal, clone DM1A, purified from hybridoma cell culture
Sigma-Aldrich
Anti-Mouse IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Ubiquitin Antibody, Lys48-Specific, clone Apu2, rabbit monoclonal, clone Apu2, from rabbit
Roche
Anti-GFP, from mouse IgG1κ (clones 7.1 and 13.1)
Sigma-Aldrich
Anti-Glyceraldehyde-3-Phosphate Dehydrogenase Antibody, clone 6C5, clone 6C5, Chemicon®, from mouse