Seed-competent tau monomer initiates pathology in a tauopathy mouse model

Mirbaha, Hilda; Chen, Dailu; Mullapudi, Vishruth; Terpack, Sandi Jo; White, Charles L.; Joachimiak, Łukasz A.; Diamond, Marc I.

doi:10.1016/j.jbc.2022.102163

Cited by 25 publications

(30 citation statements)

References 36 publications

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“…Despite this, there are no clear patterns of PTMs for tau that drive its aggregation directly and it may simply be a modification as the protein ages or conversely a mark on the pathological assemblies following their conversion into amyloid structures. Our work has shown that tau phosphorylation may occur on tau prior to disease but there is no clear signature that marks its conversion into pathological conformations that seed 17 . Interestingly, phosphorylation on tau often occurs on the periphery outside of the repeat domain required for fibril assembly.…”

Section: Discussionmentioning

confidence: 80%

“…Detection of phosphorylated tau is the de facto method for disease diagnosis in blood 23 but also for detection of tau pathology in post-mortem tissues 24,25 . Phosphorylation on tau is relatively ubiquitous but excluded from the repeat domain with the exception of AD-specific modifications on serine S262 that lie outside of the AD fibril core 17,26 . Consistent with this observation, phospho-modifications in the repeat domain inhibit tau assembly 27 .…”

Section: Introductionmentioning

confidence: 99%

“…We and others have shown that perturbation of beta-turn-based regulatory elements in a monomer can lead to the formation of a seed-competent monomer 12,13,16 . The seeding-competent monomer species can be isolated from AD patients and tauopathy mouse brains but are absent in control tissues 12,13,17 . These regulatory elements can be recapitulated with wildtype tau peptides that span the amyloid motif and the preceding sequence including the P-G-G-G motif in 4 repeat (4R) tau (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…For many years, post-translational modifications (PTMs) such as phosphorylation have been implicated in conversion of tau into pathogenic conformations 19–22 . However, recent data have suggested that phosphorylation may not be the emergent perturbation that drives the formation of the first pathogenic tau species but rather accumulates once the assemblies are formed 17 . Detection of phosphorylated tau is the de facto method for disease diagnosis in blood 23 but also for detection of tau pathology in post-mortem tissues 24,25 .…”

Section: Introductionmentioning

confidence: 99%

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Disease-associated patterns of acetylation stabilize tau fibril formation

Nguyen

Mullapudi

et al. 2023

Preprint

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Assembly of the microtubule-associated protein into tauopathy fibril conformations dictates the pathology of a diversity of diseases. Recent cryogenic Electron Microscopy (cryo-EM) structures have uncovered distinct fibril conformations in different tauopathies but it remains unknown how these structures fold from a single protein sequence. It has been proposed that post-translational modifications may drive tau assembly but no direct mechanism for how modifications drive assembly has emerged. Leveraging established aggregation-regulating tau fragments that are normally inert, we tested the effect of chemical modification of lysines with acetyl groups on tau fragment conversion into amyloid aggregates. We identify specific patterns of acetylation that flank amyloidogenic motifs on the tau fragments that drive rapid fibril assembly. To understand how this pattern of acetylation may drive assembly, we determined a 3.9 Å cryo-EM structure of an amyloid fibril assembled from an acetylated tau fragment. The structure uncovers how lysine acetylation patterns mediate gain-of-function interactions to promote amyloid assembly. Comparison of the structure to an ex vivo tau fibril conformation from Picks Disease reveals regions of high structural similarity. Finally, we show that our lysine-acetylated sequences exhibit fibril assembly activity in cell-based tau aggregation assays. Our data uncover the dual role of lysine residues in limiting aggregation while their acetylation leads to stabilizing pro-aggregation interactions. Design of tau sequence with specific acetylation patterns may lead to controllable tau aggregation to direct folding of tau into distinct folds.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disease-associated patterns of acetylation stabilize tau fibril formation

Nguyen

Mullapudi

et al. 2023

Preprint

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“…This study, together with our previous work 20,39 , emphasized the importance of exposure of the amyloid motif 306 VQIVYK 311 in aggregation and strengthened the therapeutic significance of shielding the amyloid motif to mitigate aggregation. Prior work uncovered alternate monomeric states of tau that were aggregation-prone and harbored specific patterns of amyloid motif exposure 39,40 that are detectible early in disease 41 . These insights suggest the possibility of leveraging the exposed amyloid motifs as molecular targets for developing diagnostic and therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Chen

Wosztyl

Mullapudi

et al. 2022

Preprint

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Amyloid deposition of the microtubule-associated protein tau is a unifying theme in a multitude of neurodegenerative diseases. Disease-associated missense mutations in tau are associated with frontotemporal dementia (FTD) and enhance tau aggregation propensity. However, the molecular mechanism of how mutations in tau promote tau assembly into amyloids remains obscure. There is a need to understand how tau folds into pathogenic conformations to cause disease. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation. We use recombinant protein and synthetic peptide systems, computational modeling, cross-linking mass spectrometry, and cell models to investigate the mechanism of spontaneous aggregation of the S320F FTD-tau mutant. We discover that the S320F mutation drives the stabilization of a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif. We identify a suppressor mutation that reverses the S320F aggregation phenotype through the reduction of S320F-based hydrophobic clustering in vitro and in cells. Finally, we use structure-based computational design to engineer rapidly aggregating tau sequences by optimizing nonpolar clusters in proximity to the S320 site revealing a new principle that governs the regulation of tau aggregation. We uncover a mechanism for regulating aggregation that balances transient nonpolar contacts within local protective structures or in longer-range interactions that sequester amyloid motifs. The introduction of a pathogenic mutation redistributes these transient interactions to drive spontaneous aggregation. We anticipate deeper knowledge of this process will permit control of tau aggregation into discrete structural polymorphs to aid design of reagents that can detect disease-specific tau conformations.

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Travels with tau prions

Diamond

2023

Cytoskeleton

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Tau was originally identified as a microtubule associated protein, and subsequently recognized to constitute the fibrillar assemblies found in Alzheimer disease and related neurodegenerative tauopathies. Point mutations in the microtubule associated protein tau (MAPT) gene cause dominantly inherited tauopathies, and most predispose it to aggregate. This indicates tau aggregation underlies pathogenesis of tauopathies. Our work has suggested that tau functions as a prion, forming unique intracellular pathological assemblies that subsequently move to other cells, inducing further aggregation that underlies disease progression. Remarkably, in simple cells tau forms stably propagating aggregates of distinct conformation, termed strains. Each strain induces a unique and, in some cases, transmissible, neuropathological phenotype upon inoculation into a mouse model. After binding heparan sulfate proteoglycans on the plasma membrane, tau assemblies enter cells via macropinocytosis. From within a vesicle, if not trafficked to the endolysosomal system, tau subsequently enters the cytoplasm, where it becomes a template for its own replication, apparently after processing by valosin containing protein. The smallest seed unit is a stable monomer, which suggests that initial folding events in tau presage subsequent pathological aggregation. The study of tau prions has raised important questions about basic cell biological processes that underlie their replication and propagation, with implications for therapy of tauopathies.

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Seed-competent tau monomer initiates pathology in a tauopathy mouse model

Cited by 25 publications

References 36 publications

Disease-associated patterns of acetylation stabilize tau fibril formation

Disease-associated patterns of acetylation stabilize tau fibril formation

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Travels with tau prions

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