Seeding of proteins into amyloid structures by metabolite assemblies may clarify certain unexplained epidemiological associations

Sade, Dorin; Shaham-Niv, Shira; Arnon, Zohar A.; Tavassoly, Omid; Gazit, Ehud

doi:10.1098/rsob.170229

Cited by 29 publications

(26 citation statements)

References 84 publications

(135 reference statements)

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“…It is possible that some fibril polymorphs require mixtures of different tau isoforms to efficiently propagate (25), although in our hands, seeding mixtures of K18ϩ and K19ϩ (3R and 4R tau) did not dramatically improve the fidelity of seeding. Or, as recently proposed, amyloid formation may be steered by cellular co-factors and/or metabolites (28). In support of this, brain-derived CTE fibrils apparently enclose a hydrophobic molecule that may be necessary for faithful replication during in vitro seeding (12).…”

Section: Inhibitors Block Seeding By Disease-associated Tau Fibrilsmentioning

confidence: 58%

Structure-based inhibitors halt prion-like seeding by Alzheimer’s disease–and tauopathy–derived brain tissue samples

Seidler¹,

Boyer²,

Murray³

et al. 2019

Journal of Biological Chemistry

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In Alzheimer's disease (AD) and tauopathies, tau aggregation accompanies progressive neurodegeneration. Aggregated tau appears to spread between adjacent neurons and adjacent brain regions by prion-like seeding. Hence, inhibitors of this seeding offer a possible route to managing tauopathies. Here, we report the 1.0 Å resolution micro-electron diffraction structure of an aggregation-prone segment of tau with the sequence SVQIVY, present in the cores of patient-derived fibrils from AD and tauopathies. This structure illuminates how distinct interfaces of the parent segment, containing the sequence VQIVYK, foster the formation of distinct structures. Peptide-based fibril-capping inhibitors designed to target the two VQIVYK interfaces blocked proteopathic seeding by patient-derived fibrils. These VQIVYK inhibitors add to a panel of tau-capping inhibitors that targets specific polymorphs of recombinant and patient-derived tau fibrils. Inhibition of seeding initiated by brain tissue extracts differed among donors with different tauopathies, suggesting that particular fibril polymorphs of tau are associated with certain tauopathies. Donors with progressive supranuclear palsy exhibited more variation in inhibitor sensitivity, suggesting that fibrils from these donors were more polymorphic and potentially vary within individual donor brains. Our results suggest that a subset of inhibitors from our panel could be specific for particular disease-associated polymorphs, whereas inhibitors that blocked seeding by extracts from all of the tauopathies tested could be used to broadly inhibit seeding by multiple disease-specific tau polymorphs. Moreover, we show that tau-capping inhibitors can be transiently expressed in HEK293 tau biosensor cells, indicating that nucleic acid-based vectors can be used for inhibitor delivery. Tau pathology is a marker of neurodegeneration both in AD, 2 which is accompanied by deposits of aggregated ␤-amyloid, and pure tauopathies, which lack aggregated ␤-amyloid (1, 2). The spreading of minimal units of tau pathology-aggregates of tau, termed seeds-converts inert, soluble tau monomers in recipient cells into pathological aggregates through a process called prion-like seeding, in principle connecting seeding to the progressive cascade of neurodegeneration that is characteristic of tauopathies and AD (2-5). The amyloid core of tau, like other amyloidogenic proteins, is formed by steric zippers with rich ␤ character, tightly interdigitated side chains, and strong shape complementarity (6, 7). Amyloid structures are particularly stable relative to other protein folds owing to steric zipper interactions and an extensive network of hydrogen bonds that forms along the fibril axis (8, 9), potentially explaining their ability to spread transcellularly to distant, but anatomically connected, brain regions. Often the aggregation of amyloid proteins results in a given sequence forming different folds-structural polymorphsthat are associated with different neurodegenerative diseases. For tau, this is exemplif...

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Section: Inhibitors Block Seeding By Disease-associated Tau Fibrilsmentioning

confidence: 58%

Structure-based inhibitors halt prion-like seeding by Alzheimer’s disease–and tauopathy–derived brain tissue samples

Seidler¹,

Boyer²,

Murray³

et al. 2019

Journal of Biological Chemistry

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“…348 It was suggested that the presence of metabolite seeds could have a triggering effect on the eruption of amyloid-associated neurodegenerative disorders. 349 Indeed, it was shown that quinolinic acid, a wellestablished early marker of PD, could seed the aggregation of aS into amyloid fibrils. 340 This may provide the missing link between the metabolite profile and the development of various degenerative processes and may clarify certain unexplained epidemiological associations.…”

Section: Metabolite Amyloidosismentioning

confidence: 99%

“…340 This may provide the missing link between the metabolite profile and the development of various degenerative processes and may clarify certain unexplained epidemiological associations. 349 All of the experiments in metabolite amyloids until 2019 have been performed in vitro or in cell culture. It was recently demonstrated that a yeast model of metabolite aggregation could be constructed.…”

Section: Metabolite Amyloidosismentioning

confidence: 99%

Half a century of amyloids: past, present and future

et al. 2020

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“…In this study, we aimed to test our recently presented hypothesis in which we propose that metabolite accumulation and supramolecular structure formation is a fundamental mechanism that may contribute to the initial steps inducing toxicity of amyloids and consequent neurodegeneration [53]. We postulate that these metabolite assemblies can serve as nuclei that crossseed protein aggregation, thereby accelerating formation of pathological deposits of aggregation-prone proteins such as tau, β-amyloid and α-synuclein.…”

Section: Introductionmentioning

confidence: 99%

Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation

Tavassoly

Sade

Bera

et al. 2018

Journal of Molecular Biology

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Quinolinic acid (QA), a downstream neurometabolite in the kynurenine pathway, the biosynthetic pathway of tryptophan, is associated with neurodegenerative diseases pathology. Mutations in genes encoding kynurenine pathway enzymes, which control the level of QA production, are linked with elevated risk of developing Parkinson's disease. Recent findings have revealed the accumulation and deposition of QA in post-mortem samples, as well as in cellular models of Alzheimer's disease and related disorders. Furthermore, intrastriatal inoculation of mice with QA results in increased levels of phosphorylated α-synuclein and neurodegenerative pathological and behavioral characteristics. However, the cellular and molecular mechanisms underlying the involvement of QA accumulation in protein aggregation and neurodegeneration remain elusive. We recently established that self-assembled ordered structures are formed by various metabolites and hypothesized that these "metabolite amyloids" may seed amyloidogenic proteins. Here we demonstrate the formation of QA amyloid-like fibrillar assemblies and seeding of α-synuclein aggregation by these nanostructures both in vitro and in cell culture. Notably, α-synuclein aggregation kinetics was accelerated by an order of magnitude. Additional amyloid-like properties of QA assemblies were demonstrated using thioflavin T assay, powder X-ray diffraction and cell apoptosis analysis. Moreover, fluorescently labeled QA assemblies were internalized by neuronal cells and co-localized with α-synuclein aggregates. In addition, we observed cell-to-cell propagation of fluorescently labeled QA assemblies in a co-culture of treated and untreated cells. Our findings suggest that excess QA levels, due to mutations in the kynurenine pathway, for example, may lead to the formation of metabolite assemblies that seed α-synuclein aggregation, resulting in neuronal toxicity and induction of Parkinson's disease.

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Seeding of proteins into amyloid structures by metabolite assemblies may clarify certain unexplained epidemiological associations

Cited by 29 publications

References 84 publications

Structure-based inhibitors halt prion-like seeding by Alzheimer’s disease–and tauopathy–derived brain tissue samples

Structure-based inhibitors halt prion-like seeding by Alzheimer’s disease–and tauopathy–derived brain tissue samples

Half a century of amyloids: past, present and future

Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation

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