Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

Abstract

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. 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. Amyloid deposits are characteristic of various neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Typically, symptoms surface only at advanced age, indicating that a buffering system exists that prevents disease onset and amyloid formation earlier in life (1Labbadia J. Morimoto R.I. The biology of proteostasis in aging and disease.Annu. Rev. Biochem. 2015; 84 (25784053): 435-46410.1146/annurev-biochem-060614-033955Crossref PubMed Scopus (764) Google Scholar). Disease-associated proteins aggregate into amyloid fibrils characterized by their highly ordered β-sheet structure (2Chiti F. Dobson C.M. Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade.Annu. Rev. Biochem. 2017; 86 (28498720): 27-6810.1146/annurev-biochem-061516-045115Crossref PubMed Scopus (1418) Google Scholar). The monomeric form of these proteins populates conformations susceptible to aggregation, leading to the formation of a variety of assemblies of various molecular weights. Some have seeding propensities that trigger further aggregation into fibrils by templated incorporation of the monomeric form of the constituting protein in a conformation that is compatible with the fibril ends. This templated propagation of the amyloid structure is thought to be the basis for the prion-like spreading of pathological inclusions and toxicity in neurodegenerative diseases (3Brundin P. Melki R. Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases.Nat. Rev. Mol. Cell Biol. 2010; 11 (20308987): 301-30710.1038/nrm2873Crossref PubMed Scopus (566) Google Scholar). The aggregation of the microtubule-associated protein Tau is implicated in ∼20 different diseases, termed tauopathies, with AD being the most common form of dementia (4Spillantini M.G. Goedert M. Tau pathology and neurodegeneration.Lancet Neurol. 2013; 12 (23684085): 609-62210.1016/S1474-4422(13)70090-5Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar). Thus, Tau is the most frequently aggregating protein in human neurodegenerative diseases. Under physiological conditions, Tau is highly soluble and expressed as six alternatively spliced isoforms (5Goedert M. Spillantini M.G. Jakes R. Rutherford D. Crowther R.A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease.Neuron. 1989; 3 (2484340): 519-52610.1016/0896-6273(89)90210-9Abstract Full Text PDF PubMed Scopus (1852) Google Scholar). It binds and supports the assembly of microtubules that are vital for axonal transport in neurons (6Mandelkow E.M. Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration.Cold Spring Harb. Perspect. Med. 2012; 2 (22762014): a00624710.1101/cshperspect.a006247Crossref PubMed Scopus (2) Google Scholar). Under pathological conditions, the affinity of Tau to microtubules is reduced, either by disease-associated mutations J. Mandelkow E.M. Mandelkow E. of of tau to and 11 Full Text PDF PubMed Scopus Google in Alzheimer’s disease and Rev. PubMed Scopus Google M. E. E. the spreading of Full Text Full Text PDF PubMed Scopus Google Scholar). Tau aggregates in the that into inclusions in neurons (4Spillantini M.G. Goedert M. Tau pathology and neurodegeneration.Lancet Neurol. 2013; 12 (23684085): 609-62210.1016/S1474-4422(13)70090-5Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar). the of Tau and other proteins is by a protein molecular chaperones (1Labbadia J. Morimoto R.I. The biology of proteostasis in aging and disease.Annu. Rev. Biochem. 2015; 84 (25784053): 435-46410.1146/annurev-biochem-060614-033955Crossref PubMed Scopus (764) Google of amyloid by molecular Spring Harb. Perspect. Biol. PubMed Scopus Google of proteostasis in aging and Cell Biol. PubMed Scopus Google Scholar). This system the by the and of proteins to their as well as the and of molecular chaperones at of the amyloid formation and of amyloid by molecular Spring Harb. Perspect. Biol. PubMed Scopus Google for protein and Rev. Mol. Cell Biol. 2013; PubMed Scopus Google The chaperone proteins as of Rev. Mol. Cell Biol. 2010; 11 PubMed Scopus Google D. M. of protein and PubMed Scopus Google R. The Hsp70 chaperone Rev. Mol. Cell Biol. PubMed Scopus Google Scholar). have molecular chaperone to Tau aggregation in and in It that heat shock protein of J-domain protein cochaperones, and the small heat shock protein Tau fibril formation J. J. D. M. of in tau 2010; PubMed Scopus Google R. J. J. M. with the chaperone that tau Mol. Biol. PubMed Scopus Google shock protein prevents tau aggregation and the of tau aggregates axonal PubMed Scopus Google Hsp70 tau function and aggregation in an specific 2012; PubMed Scopus Google Scholar). Hsp70 chaperones with oligomeric Tau and further aggregation into fibrils shock protein prevents tau aggregation and the of tau aggregates axonal PubMed Scopus Google Scholar). only of Tau fibrils by Hsp70 activity shock protein prevents tau aggregation and the of tau aggregates axonal PubMed Scopus Google Hsp70 tau function and aggregation in an specific 2012; PubMed Scopus Google Scholar). and other that Hsp70 disaggregation activity a of an Hsp70 core chaperone with specific The chaperone proteins as of Rev. Mol. Cell Biol. 2010; 11 PubMed Scopus Google R. The Hsp70 chaperone Rev. Mol. Cell Biol. PubMed Scopus Google Scholar). the of chaperones and Tau amyloid fibrils and in only the of aggregation and a of the amyloid the soluble of their to specific disaggregation activity of Tau a of chaperone and be to the of aggregation and disaggregation activity by chaperones in in which is J-domain proteins to Hsp70 by and their into the of of the exchange the of the which such as to other chaperone to the machinery J. The nucleotide exchange of Hsp70 molecular Mol. 2015; PubMed Scopus Google Scholar). the of chaperones and that Tau fibrils is Here, we that the human Hsp70 disaggregation to as Hsp70 amyloid Tau fibrils in vitro. The Hsp70 is an ATP-dependent chaperone system that is of the expressed Hsp70 the J-domain proteins and an fibrils of all six Tau as well as Sarkosyl-resistant Tau aggregates extracted from a cell culture AD brain be processed by this chaperone demonstrating that this chaperone machinery We further show that class B J-domain proteins are for this activity and that is this class of class J-domain proteins to Hsp70 The disaggregation monomeric Tau as well as small Tau by the disaggregation seeding and induced the formation of Tau in a cell for Tau aggregation, which over cell This that Hsp70 activity be to the most neurodegenerative diseases to the of Tau that released from amyloid fibrils by chaperone seeding the of the prion-like propagation of amyloid Tau it to be Tau disaggregation the in We have that the human Hsp70 of HSC70, and fibrils in M. Hsp70 amyloid 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). Tau fibrils be by this chaperone we in disaggregation M. Hsp70 amyloid 2015; Full Text Full Text PDF PubMed Scopus Google and assembled into and fibril formation by transmission Tau fibrils with the human Hsp70 disaggregation machinery and to fibrils from and The of Tau in and by and the of the chaperones and of Tau in the and in the of the chaperone disaggregation activity and The of the Hsp70 disaggregation machinery and in all to their to fibril and with of chaperones a of Tau to the with which in of of Tau to the and However, the of all chaperones for the most disaggregation leading to and indicating a of the in Tau fibril the human disaggregation machinery disassembles a of Tau fibrils in vitro. Tau six different isoforms that are by (5Goedert M. Spillantini M.G. Jakes R. Rutherford D. Crowther R.A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease.Neuron. 1989; 3 (2484340): 519-52610.1016/0896-6273(89)90210-9Abstract Full Text PDF PubMed Scopus (1852) Google all isoforms found in aggregates from AD are amyloid deposits of either Tau isoforms (4Spillantini M.G. Goedert M. Tau pathology and neurodegeneration.Lancet Neurol. 2013; 12 (23684085): 609-62210.1016/S1474-4422(13)70090-5Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar). Tau in disease only is characterized by fibrils of all six isoforms are for the disaggregation recombinant fibrils of the other Tau isoforms and to and the by to fibrils by all other Tau isoforms be by the human disaggregation with and all isoforms disaggregation their with Tau fibrils being most and fibrils being most to disaggregation these show that the Hsp70 disaggregation activity all Tau and is to fibrils assembled from a Tau Amyloid aggregates in different in as with other proteins the F. J. J. E. M. The tau molecular we the into new for PubMed Scopus Google Scholar). Tau aggregates in are of the human Hsp70 disaggregation we of a cell of Tau aggregation M. D. Goedert M. tau 2017; PubMed Scopus Google Scholar). This cell Tau which soluble and as a for Tau seeding M. D. Goedert M. tau 2017; PubMed Scopus Google Scholar). the with recombinant fibrils from the Tau we the and to a of Tau aggregates that in The Sarkosyl-resistant extracted from the and to in disaggregation the of HSC70, and of the in the and we Tau be by the Hsp70 disaggregation We Tau from AD and as M. pathological tau conformers from Alzheimer’s tau pathology in Med. PubMed Scopus Google Tau in this with the disaggregation machinery in released of Tau into the and these that the human Hsp70 disaggregation machinery is of which in a human cell culture as well as pathological Tau extracted from the brain of an AD Hsp70 is mediated by J-domain proteins that recognize chaperone and to Hsp70 The chaperone proteins as of Rev. Mol. Cell Biol. 2010; 11 PubMed Scopus Google Scholar). different J-domain into and with and localization The chaperone proteins as of Rev. Mol. Cell Biol. 2010; 11 PubMed Scopus Google R. The Hsp70 chaperone Rev. Mol. Cell Biol. PubMed Scopus Google Scholar). class and B J-domain proteins are in the brain aging and in neurodegenerative diseases M. D. M. Morimoto R.I. proteostasis in aging and neurodegenerative Full Text Full Text PDF PubMed Scopus Google Scholar). the class as well as the class B are in with and disease with M. D. M. 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D. Goedert M. tau 2017; PubMed Scopus Google Scholar). The to this for and the of by The of Tau fibrils with the disaggregation machinery and formation in of of the of the chaperones of the disaggregation machinery and with and and monomeric Tau induced with fibrils to the accumulation of indicating that formation templated We further the propagation of the Tau species, the of Tau in to the Tau released by chaperone Tau in cell demonstrating that Tau by the Hsp70 disaggregation machinery only seeding to aggregate that in Tau fibril by the human Hsp70 disaggregation machinery as well as and Tau species, which seeding and induced self-propagating Tau conformers in an cell culture for Tau It is well that the of molecular chaperones in all of protein from of to the of protein aggregates and of proteins (1Labbadia J. Morimoto R.I. The biology of proteostasis in aging and disease.Annu. Rev. Biochem. 2015; 84 (25784053): 435-46410.1146/annurev-biochem-060614-033955Crossref PubMed Scopus (764) Google of amyloid by molecular Spring Harb. Perspect. Biol. PubMed Scopus Google of proteostasis in aging and Cell Biol. PubMed Scopus Google Scholar). disease which is be a However, it to chaperones are of their J. M. Dobson C.M. of proteins and the of amyloid PubMed Scopus Google Scholar). for and it that the human Hsp70 machinery fibrils in M. Hsp70 amyloid 2015; Full Text Full Text PDF PubMed Scopus Google M. D. J. J. of and disaggregation of fibrils by a chaperone J. PubMed Scopus Google Scholar). Here, we the of this machinery in amyloid biology by to aggregates of Tau from AD from a cell culture in and by the of Tau This is Tau aggregation is to the most human neurodegenerative diseases, and a in brain (4Spillantini M.G. Goedert M. Tau pathology and neurodegeneration.Lancet Neurol. 2013; 12 (23684085): 609-62210.1016/S1474-4422(13)70090-5Abstract Full Text Full Text PDF PubMed Scopus (731) Google R.A. C.M. of disease in 2013; PubMed Scopus Google Scholar). We show that the Hsp70 disaggregation machinery is of in Tau amyloid fibrils as well as Sarkosyl-resistant Tau aggregates in cell pathological Tau extracted from human AD brain demonstrating that this chaperone protein Tau disaggregation in a accumulation of Tau and of the Tau that it monomeric and oligomeric with molecular of and compatible with that of and this seeding as it induced self-propagating aggregates of a expressed Tau in a cell culture that Tau disaggregation is be in the prion-like propagation of Tau it be to further the of the Tau and to the of the Amyloid fibrils a common core structure of a characteristic conformation P. P. The common of Mol. Biol. 2010; PubMed Scopus Google Scholar). a fibrils of and Tau different surface as R. 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