Prion-like strain effects in tauopathies

Han, Zhuang Zhuang; Kang, Sang Gyun; Arce, Luis; Westaway, David

doi:10.1007/s00441-022-03620-1

Cited by 17 publications

(10 citation statements)

References 203 publications

(213 reference statements)

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“…The microtubule-associated protein tau deposits into β-sheetrich amyloids in over 25 neurodegenerative diseases commonly referred to as tauopathies that include Alzheimer's disease (AD), Corticobasal degeneration (CBD), Picks disease (PiD), and Chronic traumatic encephalopathy (CTE) [1][2][3] . In sporadic cases of tauopathies, the wild-type (WT) sequence of the microtubule-associated protein tau gene (MAPT) is linked to each disease.…”

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confidence: 99%

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

et al. 2023

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Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.

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confidence: 99%

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

et al. 2023

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“…gation is primarily driven by the presence of polyanionic inducers (Ingham et al, 2022) or specific combinations of salt ingredients (Lövestam et al, 2022)-the physiological relevance of these findings will need to be validated in human patient samples and in animal models. To the best of our knowledge, despite that many ageing tauopathies (reviewed by [Han et al, 2022]). A future model should thus be expected to exhibit heterogeneity of tau conformers at an advanced biological age, similar to a low-tau expression transgenic mouse model previously reported (Daude et al, 2020;Eskandari-Sedighi et al, 2017).…”

Section: Naked Mole Ratmentioning

confidence: 99%

“…The wide range of lifespan of these models (ranging from <1 month for C. elegans to potential immortality for S. mediterranea ) may help gain a more holistic understanding of the ageing process in the nervous tissues. It should be noted that tau misfolding may give rise to structurally distinct pathogenic species in different tauopathies (reviewed by [Han et al, 2022 ]). A future model should thus be expected to exhibit heterogeneity of tau conformers at an advanced biological age, similar to a low‐tau expression transgenic mouse model previously reported (Daude et al, 2020 ; Eskandari‐Sedighi et al, 2017 ).…”

Section: Ageing Model Organisms In Neurodegeneration Researchmentioning

confidence: 99%

Can accelerated ageing models inform us on age‐related tauopathies?

2023

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Ageing is the greatest risk factor of late‐onset neurodegenerative diseases. In the realm of sporadic tauopathies, modelling the process of biological ageing in experimental animals forms the foundation of searching for the molecular origin of pathogenic tau and developing potential therapeutic interventions. Although prior research into transgenic tau models offers valuable lessons for studying how tau mutations and overexpression can drive tau pathologies, the underlying mechanisms by which ageing leads to abnormal tau accumulation remains poorly understood. Mutations associated with human progeroid syndromes have been proposed to be able to mimic an aged environment in animal models. Here, we summarise recent attempts in modelling ageing in relation to tauopathies using animal models that carry mutations associated with human progeroid syndromes, or genetic elements unrelated to human progeroid syndromes, or have exceptional natural lifespans, or a remarkable resistance to ageing‐related disorders.

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“…Adding to the complexity, different pathological conformations of the same protein not only can result in variable degrees of toxicity but may also target very different parts of the nervous system, leading to the concept of differing “strains” of a misfolded protein. − Initially discovered in the field of prion disorders, this “strain hypothesis” has been extended to other neurodegenerative diseases, including AD, PD, and tauopathies. − Therefore, a protein with one physiological conformation can misfold into several pathological conformations, generating oligomers with different toxic properties and subsequently assembling into structurally distinct amyloid fibrils (Figure ). Interestingly, the presence of different misfolded protein strains has been found to correlate with various clinical phenotypes, ,,− implying that eventual treatment strategies aimed at a causative species of misfolded protein may have to be matched to the specific subtype of pathology observed.…”

Section: Introductionmentioning

confidence: 99%

Spectral Fluorescence Pathology of Protein Misfolding Disorders

Stepanchuk,

Stys

2024

ACS Chem. Neurosci.

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Protein misfolding has been extensively studied in the context of neurodegenerative disorders and systemic amyloidoses. Due to misfolding and aggregation of proteins being highly heterogeneous and generating a variety of structures, a growing body of evidence illustrates numerous ways how the aggregates contribute to progression of diseases such as Alzheimer's disease, Parkinson's disease, and prion disorders. Different misfolded species of the same protein, commonly referred to as strains, appear to play a significant role in shaping the disease clinical phenotype and clinical progression. The distinct toxicity profiles of various misfolded proteins underscore their importance. Current diagnostics struggle to differentiate among these strains early in the disease course. This review explores the potential of spectral fluorescence approaches to illuminate the complexities of protein misfolding pathology and discusses the applications of advanced spectral methods in the detection and characterization of protein misfolding disorders. By examining spectrally variable probes, current data analysis approaches, and important considerations for the use of these techniques, this review aims to provide an overview of the progress made in this field and highlights directions for future research.

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Prion-like strain effects in tauopathies

Cited by 17 publications

References 203 publications

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

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

Can accelerated ageing models inform us on age‐related tauopathies?

Spectral Fluorescence Pathology of Protein Misfolding Disorders

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