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-Structure paper
タイトル | The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 560, Year 2023 |
掲載日 | 2023年2月2日 |
![]() | 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 / ![]() ![]() ![]() ![]() ![]() |
PubMed 要旨 | 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 ...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. |
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手法 | EM (トモグラフィー) |
構造データ | ![]() EMDB-13739: Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing Hek293T cell ![]() EMDB-13740: Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing primary mouse neuron |
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