Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species
In: Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2020, pp.jbc.RA120.013478. ⟨10.1074/jbc.RA120.013478⟩ The Journal of Biological Chemistry Journal of Biological Chemistry, 2020, 295, pp.9676-9690. ⟨10.1074/jbc.ra120.013478⟩ Journal of Biological Chemistry, 295(28), 9676-9690. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC Journal of Biological Chemistry, 2020, pp.jbc.RA120.013478. ⟨10.1074/jbc.RA120.013478⟩; (2020-05-28)
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International audience; The accumulation of amyloid Tau aggregates is implicated in Alzheimer’s disease (AD) and other tauopathies. Molecular chaperones are known to maintain protein homeostasis. Here, we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro. We found that this function is mediated by the core chaperone HSC70, assisted by specific cochaperones, in particular class B J-domain proteins and a heat shock protein 110 (Hsp110)-type nucleotide exchange factor (NEF). The Hsp70 disaggregation machinery processed recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell cultures and human AD brain tissues, demonstrating the ability of the Hsp70 machinery to recognize a broad range of Tau aggregates. However, the chaperone activity released monomeric and small oligomeric Tau species, which induced the aggregation of self-propagating Tau conformers in a Tau cell culture model. We conclude that the activity of the Hsp70 disaggregation machinery is a double-edged sword, as it eliminates Tau amyloids at the cost of generating new seeds.
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Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species
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Autor/in / Beteiligte Person: | Madiona, Karine ; Mogk, Axel ; Katsinelos, Taxiarchis ; Nachman, Eliana ; Bukau, Bernd ; Kampinga, Harm H. ; Bousset, Luc ; Wentink, Anne S. ; Allinson, Kieren ; Melki, Ronald ; McEwan, William A. ; Jahn, Thomas R. ; Nussbaum-Krammer, Carmen ; Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany] (ZMBH) ; Universität Heidelberg [Heidelberg] ; German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ) ; Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN) ; Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN) ; Université Paris-Saclay-Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) ; Department of Clinical Neurosciences [Cambridge] ; University of Cambridge [UK] (CAM) ; Cambridge University Hospitals - NHS (CUH) ; University of Groningen [Groningen] ; Universität Heidelberg [Heidelberg] = Heidelberg University ; Institut de Biologie François JACOB (JACOB) ; Service MIRCEN (MIRCEN) ; Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) ; UK Dementia Research Institute (UK DRI) ; University College of London [London] (UCL) ; University Medical Center Groningen [Groningen] (UMCG) ; ANR-17-JPCD-0005,Protest-70,Protecting protein homeostasis in synucleinopathies and tauopathies by modulating the Hsp70/co-chaperone network(2017) ; European Project: (grant No 116060),IMPRiND ; Molecular Neuroscience and Ageing Research (MOLAR) |
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Quelle: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2020, pp.jbc.RA120.013478. ⟨10.1074/jbc.RA120.013478⟩ The Journal of Biological Chemistry Journal of Biological Chemistry, 2020, 295, pp.9676-9690. ⟨10.1074/jbc.ra120.013478⟩ Journal of Biological Chemistry, 295(28), 9676-9690. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC Journal of Biological Chemistry, 2020, pp.jbc.RA120.013478. ⟨10.1074/jbc.RA120.013478⟩; (2020-05-28) |
Veröffentlichung: | HAL CCSD, 2020 |
Medientyp: | unknown |
ISSN: | 0021-9258 (print) ; 1083-351X (print) |
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