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TitleThe AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 560, Year 2023
Publish dateFeb 2, 2023
AuthorsItika 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 /
PubMed AbstractAmyloid-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 ...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.
External linksNat Commun / PubMed:36732333 / PubMed Central
MethodsEM (tomography)
Structure data

EMDB-13739: Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing Hek293T cell
Method: EM (tomography)

EMDB-13740: Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing primary mouse neuron
Method: EM (tomography)

Source
  • Homo sapiens (human)
  • Mus musculus (house mouse)

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