Heterotypic amyloid interactions: Clues to polymorphic bias and selective cellular vulnerability?

Louros, Nikolaos; Schymkowitz, Joost; Rousseau, Frédéric

doi:10.1016/j.sbi.2021.11.007

Cited by 8 publications

(5 citation statements)

References 100 publications

(77 reference statements)

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“…CBD and PSP or AD and CTE) still adopt different filament folds indicating that other factors also shape the diversity of tau filament folds 20,33 . Disease-specific post-translational modifications 31 , as well as other physiopathological cellular interactions probably play an important role for the maturation of pathological tau into disease specific polymorphs 8,34 .…”

Section: Discussionmentioning

confidence: 99%

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

Louros

Wilkinson

Tsaka

et al. 2022

Preprint

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Different tauopathies are characterized by specific amyloid filament folds that are conserved between patients. Disease-specific tau filament folds probably reflect the specific pathological contexts leading to their formation including isoforms or post-translational modifications. Little is known, however, as to whether and how intrinsic conformational tendencies of the tau sequence itself contribute to its polymorphism. Using cryo-EM structure determination we find that a short amyloidogenic C-terminal peptide consisting of residues 350-362 of the tau repeat domain adopts the same polymorphic conformations in isolation as it does in the context of major disease-associated protofilament folds. Biophysical characterisation and molecular modelling show that the amyloid conformations adopted by this peptide constitute core structural motifs stabilizing distinct disease-associated tau filament folds. In accordance this segment also contributes to the efficient propagation of human AD tau seeds in tau reporter cells while it is irrelevant to heparin-induced recombinant seeds. Our findings suggest that tau 350-362 is key to the propagation of disease-associated tau polymorphs and that the conformational preferences of this segment predispose to the topological diversity observed in tau filament folds.

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Section: Discussionmentioning

confidence: 99%

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

Louros

Wilkinson

Tsaka

et al. 2022

Preprint

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“…Thus, we ask the question whether polymorphic strains of one amyloid protein can be induced by another amyloidogenic protein. Despite evidence for cross-interactions between amyloid proteins such as those for amyloid-b (Ab) and islet amyloid polypeptide (IAPP), αS and Ab, αS and Tau (13,18,(49)(50)(51), the answer to this question remains elusive especially for αS and TDP-43.…”

Section: Introductionmentioning

confidence: 99%

Distinct neurotoxic TDP-43 fibril polymorphs can be generated by heterotypic interactions with α-synuclein

Dhakal

Robang

Bhatt

et al. 2022

Preprint

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Amyloid aggregates of specific proteins form important pathological hallmarks in many neurodegenerative diseases, defining neuronal degeneration and disease onset. Recently, increasing numbers of patients show co-morbidities and overlaps between multiple neurodegenerative diseases, presenting distinct phenotypes. Such overlaps are often accompanied by co-localizations of more than one amyloid protein, prompting the question of whether direct interactions between different amyloid proteins could generate heterotypic amyloids. To answer this question, we investigated the effect of αsynuclein (αS) on TDP43 aggregation inspired by their co-existence in pathologies such as Lewy body dementia and limbic predominant age-related TDP43 encephalopathy. We previously showed that αS and prion-like C-terminal domain (PrLD) of TDP-43 synergistically interact with one another to generate toxic heterotypic aggregates in vitro. Here, we extend these studies to investigate whether αS induces structurally and functionally distinct polymorphs of PrLD aggregates. Using αS-PrLD heterotypic aggregates generated in two different stoichiometric proportions, we show that αS can effect PrLD fibril forms. The fibril samples have distinctive residue-level structural signatures in NMR spectra, dye-binding capability, proteinase K (PK) stability, and SDS-sensitive thermal stability. By gold nanoparticle labeling and TEM, we show the presence of both αS and PrLD proteins within the same fibrils, and thus the existence of heterotypic hybrid fibrils. We also observe that S and PrLD co-localize in the cytosol of SH-SY5Y neuroblastoma cells, and show that the heterotypic PrLD fibrils selectively induce synaptic dysfunction in primary cortical neurons. These findings establish the existence of heterotypic amyloid polymorphs and provide a molecular basis for the observed overlap between synucleinopathies and TDP43 proteinopathies.

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“…The exact role of tau deposition and spreading in neuronal cell death remains unclear. It is currently suspected that tau amyloid fibrils or their precursors aberrantly interact with cellular components including lipids, nucleic acids, proteins, and other cellular components, leading to their role in functional dysregulation and cell death [8][9][10] .…”

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confidence: 99%

Local structural preferences in shaping tau amyloid polymorphism

Louros,

Wilkinson,

Tsaka

et al. 2024

Nat Commun

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Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4’s pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.

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Heterotypic amyloid interactions: Clues to polymorphic bias and selective cellular vulnerability?

Cited by 8 publications

References 100 publications

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

Distinct neurotoxic TDP-43 fibril polymorphs can be generated by heterotypic interactions with α-synuclein

Local structural preferences in shaping tau amyloid polymorphism

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