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) 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.
Titel: |
Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species
|
---|---|
Autor/in / Beteiligte Person: | Nachman, Eliana ; Wentink, Anne, S ; Madiona, Karine ; Bousset, Luc ; Katsinelos, Taxiarchis ; Allinson, Kieren ; Kampinga, Harm ; Mcewan, William, A ; Jahn, Thomas, R ; 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) ; 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) ; Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN) ; 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)-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) ; UK Dementia Research Institute (UK DRI) ; University College of London London (UCL) ; University of Cambridge UK (CAM) ; 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 |
Link: | |
Zeitschrift: | ISSN: 0021-9258, 2020 |
Veröffentlichung: | HAL CCSD ; American Society for Biochemistry and Molecular Biology, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1074/jbc.ra120.013478 |
Schlagwort: |
|
Sonstiges: |
|