Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species
In: ISSN: 0021-9258, 2020
Online
academicJournal
Zugriff:
International audience ; The accumulation of amyloid Tau aggregates is implicated in Alzheimer’s disease (AD) andother tauopathies. Molecular chaperones are known to maintain protein homeostasis. Herewe show that an ATP-dependent human chaperone system disassembles Tau fibrils invitro. We found that this function is mediated by the core chaperone HSC70, assisted byspecific co-chaperones, in particular class B J-domain proteins and a heat shock protein110 (Hsp110)-type nucleotide exchange factor (NEF). The Hsp70 disaggregation machineryprocessed recombinant fibrils assembled from all six Tau isoforms as well as sarkosylresistant 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 activityreleased monomeric and small oligomeric Tau species, which induced the aggregation of selfpropagating Tau conformers in a Tau cell culture model. We conclude that the activity of the Hsp70 disaggregation machinery is a double-sided 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: | Nachman, Eliana ; Wentink, Anne ; Madiona, Karine ; Bousset, Luc ; Katsinelos, Taxiarchis ; Allinson, Kieren ; Kampinga, Harm, H. ; Mcewan, William, A ; Jahn, Thomas ; Melki, Ronald ; Mogk, Axel ; Bukau, Bernd ; Nussbaum-Krammer, Carmen ; Center for Molecular Biology - Zentrum für Molekulare Biologie Heidelberg, Germany (ZMBH) ; Universität Heidelberg Heidelberg = Heidelberg University ; German Cancer Research Center - Deutsches Krebsforschungszentrum Heidelberg (DKFZ) ; Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN) ; Molecular Imaging Research Center Fontenay-aux-Roses (MIRCEN) ; Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-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-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) ; Department of Clinical Neurosciences Cambridge ; University of Cambridge UK (CAM) ; Cambridge University Hospitals - NHS (CUH) ; University of Groningen Groningen |
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Zeitschrift: | ISSN: 0021-9258, 2020 |
Veröffentlichung: | HAL CCSD ; American Society for Biochemistry and Molecular Biology, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1074/jbc.RA120.013478 |
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