Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

Zhang, W; Falcon, Benjamin; Murzin, Alexey G.; Fan, Jiaqin; Crowther, R. Anthony; Goedert, Michel; Scheres, Sjors H.W.

doi:10.7554/elife.43584

Cited by 369 publications

(487 citation statements)

References 77 publications

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“…The hairpin-like structure of β4-β7 in the CBD fold resembles that of β3-β6 in the Pick fold, with the exception of C322, which points inwards to form the sharp turn in the CBD fold, and which points outwards in the Pick fold. Interestingly, in all four tau filament folds from human brain, β-strands are formed by approximately the same residues ( Figure 3); this is also true of tau filaments assembled in vitro using heparin (37). It suggests a model for the diversity of tau folds, where β-strands form fixed building blocks and the loops and turns between strands provide diversity.…”

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confidence: 79%

Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy

Zhang

Tarutani

Newell

et al. 2019

Preprint

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Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances (1-3). A higher frequency of theH1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls (4,5) and genome-wide association studies have identified additional risk factors (6). By histology, astrocytic plaques are diagnostic of CBD (7,8), as are detergentinsoluble tau fragments of 37 kDa by SDS-PAGE (9). Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD) (10), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R) (11-15). This distinguishes 4R tauopathies from Pick's disease, filaments of which are made of threerepeat (3R) tau isoforms, and from Alzheimer's disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments (16). Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryomicroscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer's disease, Pick's disease and CTE (17-19). The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after 3 R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.We extracted tau filaments from the frontal cortex of three individuals with a neuropathologically confirmed diagnosis of CBD.Abundant neuronal inclusions and astrocytic plaques were stained by antibodies specific for 4R tau (Figure 1a-c) and for hyperphosphorylated tau (Figure 1e), as well as by Gallyas-Braak silver (Figure 1f). Antibodies against 3R tau failed to give specific staining (Figure 1d). By immunoblotting of sarkosyl-insoluble fractions, two major tau bands of 64 and 68 kDa were stained by an antibody specific for 4R tau, as were two minor bands of 37 kDa ( Figure 1g). Immunogold negative-stain EM with antibodies specific for the N-and C-termini of tau, as well as for R1, R2, R3 and R4, indicated that epitopes of R2, R3 and R4 form part of the ordered cores of filaments in all three cases of CBD (Extended Data Figure 1). This is consistent with the estimated lengths of trypsin-resistant cores of CBD filaments (20). Narrow and wide filaments were present (Figure 1h), in agreement with previous findings (21). Narrow filaments have a helical twist with a crossover distance of approximately 900 Å and a minimal width of 80 Å, a maximal width of 130 Å. Wide filaments have a crossover distance of donating brain tissues; F. Epperson, R.M. Richardson and U. Kuederli for brain collection and technical support with neuropathology; G. Cannone, S. Chen, J. Brown, G. Sharov, and A. Yeates f...

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confidence: 79%

Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy

Zhang

Tarutani

Newell

et al. 2019

Preprint

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Section: Discussionmentioning

confidence: 99%

“…and 2N4R Tau vary in their architecture (Zhang et al, 2019). The ordered core of 2N3R Tau fibrils comprises the R3 repeat of two parallel Tau molecules, whereas 2N4R Tau fibrils adopt several conformations with a core consisting of R2 and R3 β strands of the same molecule (Zhang et al, 2019). Intriguingly, these differences in fibril architecture may lead to a different stability of 3R and 4R Tau fibrils, which may explain their varying susceptibility to the human Hsp70 disaggregation machinery.…”

Section: Discussionmentioning

confidence: 99%

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

Nachman

Wentink

Madiona

et al. 2019

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The accumulation of amyloid Tau aggregates is implicated in Alzheimer’s disease and other Tauopathies. Molecular chaperones are known for their function in maintaining protein homeostasis by preventing the formation or promoting the disaggregation of amorphous and amyloid protein aggregates. Here we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro. This function is mediated by the core chaperone Hsc70, assisted by specific co-chaperones, in particular class B J-domain proteins and an Hsp110-type NEF. Recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell culture were processed by the Hsp70 disaggregation machinery, demonstrating the ability of this machinery to recognize a broad range of Tau aggregates. Chaperone treatment released monomeric, and small oligomeric Tau species, which induced the aggregation of self-propagating Tau species in a Tau cell culture model. We infer from these results that the activity of the Hsp70 disaggregation machinery is a double-sided sword as it attempts to eliminate Tau amyloids but with the price of generating new seeds. The Hsp70 disaggregase therefore has a crucial function in the Tau propagation cycle, rendering it a potential drug target in Tauopathies.

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“…This could possibly explain the drastic decrease in the aggregation This clearly indicates the cumulative effect of the three phosphorylation sites on the inhibition of fibrillization. It is noteworthy that despite the fact that the R1 repeat is not part of the core of ex vivo filaments 39 , several studies have consistently shown that sequence motifs within these region associated with disease-associated mutations 40 , PTMs 41 or other sequence perturbations significantly alter the kinetics and aggregation properties of tau. Our results show that phosphorylation within the MTBD inhibits tau fibril formation, which is contrary to the conventional wisdom that this enhances tau aggregation and fibrillization.…”

Section: Discussionmentioning

confidence: 99%

Site-specific hyperphosphorylation of tau inhibits its fibrillization in vitro, blocks its seeding capacity in cells, and disrupts its microtubule binding; Implications for the native state stabilization of tau

Lashuel

Haj‐Yahya

Pushparathinam

et al. 2019

Preprint

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The consistent observation of aggregated phosopho-tau in the pathology of Alzheimer's disease and other tauopathies has contributed to the emergence of a model where hyperphosphorylation of tau causes its disassociation from microtubules and subsequent pathological polymerization. However, the large number of possible phosphorylation sites in tau and lack of robust methods that enable the preparation of homogeneously phosphorylated tau species have made it difficult to validate this model. Herein, we applied a total chemical synthetic approach to site-specifically phosphorylate single (pS356) or multiple (pS356/pS262 and pS356/pS262/pS258) residues within the microtubule binding repeat domain (MTBD) of tau and show that hyperphosphorylation within the microtubule MTBD inhibits K18 tau 1) aggregation in vitro; 2) its seeding activity in cells, and 3) its ability to promote microtubule polymerization. The inhibition increased with the number of phosphorylated sites, with phosphorylation at S262 having the strongest effect. On the basis of these findings, we propose that targeting the kinases that regulate phosphorylation at these sites could provide a viable strategy to stabilize the native state of tau and inhibit its aggregation. Taken together, our results argue against the pathogenic hyperphosphorylation hypothesis and underscore the critical importance of revisiting the role of site-specific hyperphosphorylation of tau in regulating its function in health and disease.Hilal A. Lashuel is the founder and CSO of ND BioSciences. Corresponding authorCorrespondence to Hilal A. Lashuel.

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Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

Cited by 369 publications

References 77 publications

Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy

Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy

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

Site-specific hyperphosphorylation of tau inhibits its fibrillization in vitro, blocks its seeding capacity in cells, and disrupts its microtubule binding; Implications for the native state stabilization of tau

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