ジャーナル: Nat Commun / 年: 2023 タイトル: The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system. 著者: Itika Saha / Patricia Yuste-Checa / Miguel Da Silva Padilha / Qiang Guo / Roman Körner / Hauke Holthusen / Victoria A Trinkaus / Irina Dudanova / Rubén Fernández-Busnadiego / Wolfgang ...著者: 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 / 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.
A: 13516.8 Å / B: 13066.24 Å / C: 2844.16 Å α=β=γ: 90.0 °
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添付データ
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試料の構成要素
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全体 : Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing prima...
全体
名称: Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing primary mouse neuron
要素
細胞: Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing primary mouse neuron
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超分子 #1: Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing prima...
超分子
名称: Tomogram of a TauRD-YFP aggregate in a TauRD-YFP expressing primary mouse neuron タイプ: cell / ID: 1 / 親要素: 0 / 含まれる分子: #1
由来(天然)
生物種: Mus musculus (ハツカネズミ) / 器官: brain
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実験情報
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構造解析
手法
クライオ電子顕微鏡法
解析
電子線トモグラフィー法
試料の集合状態
cell
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試料調製
緩衝液
pH: 7.2
凍結
凍結剤: ETHANE-PROPANE
切片作成
集束イオンビーム - 装置: OTHER / 集束イオンビーム - イオン: OTHER / 集束イオンビーム - 電圧: 30 kV / 集束イオンビーム - 電流: 0.1 nA / 集束イオンビーム - 時間: 1800 sec. / 集束イオンビーム - 温度: 90 K / 集束イオンビーム - Initial thickness: 1000 nm / 集束イオンビーム - 最終 厚さ: 100 nm 集束イオンビーム - 詳細: The value given for _em_focused_ion_beam.instrument is FIB Quanta. This is not in a list of allowed values {'DB235', 'OTHER'} so OTHER is written into the XML file.
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電子顕微鏡法
顕微鏡
FEI TITAN KRIOS
撮影
フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 平均電子線量: 110.0 e/Å2
電子線
加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN
電子光学系
照射モード: OTHER / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 6.0 µm / 最小 デフォーカス(公称値): 5.0 µm