1. Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species
- Author
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Karine Madiona, Axel Mogk, Taxiarchis Katsinelos, Eliana Nachman, Bernd Bukau, Harm H. Kampinga, Luc Bousset, Anne S. Wentink, Kieren Allinson, Ronald Melki, William A. McEwan, Thomas R. Jahn, Carmen Nussbaum-Krammer, 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, and Molecular Neuroscience and Ageing Research (MOLAR)
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0301 basic medicine ,70 kilodalton heat shock protein (Hsp70) ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,PROTEIN ,Protein aggregation ,Biochemistry ,Nucleotide exchange factor ,neurodegenerative disease ,BINDING ,PHOSPHORYLATION ,biology ,Chemistry ,Brain ,amyloid ,Molecular Bases of Disease ,ASSOCIATION ,JBC Keywords: Tau protein (Tau) ,molecular chaperone ,Cell biology ,ALZHEIMERS-DISEASE ,chaperone DNAJ (DNAJ) ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Tauopathy ,Amyloid ,Tau protein ,tau Proteins ,protein aggregation ,prion ,03 medical and health sciences ,Alzheimer Disease ,Heat shock protein ,mental disorders ,medicine ,Humans ,HSP70 Heat-Shock Proteins ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Molecular Biology ,proteostasis ,030102 biochemistry & molecular biology ,tauopathy ,Cell Biology ,70-kilodalton heat shock protein (Hsp70) ,AGGREGATION ,medicine.disease ,GENE-EXPRESSION CHANGES ,PATHOLOGY ,030104 developmental biology ,Proteostasis ,HEK293 Cells ,Chaperone (protein) ,biology.protein ,Tau ,MEDIATE ,HSP110 - Abstract
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.
- Published
- 2020
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