Biology subjects

Collinge, J.

Publications and source records attributed to Collinge, J..

17 recordsLinked to original sources

bioRxiv2026

Structural evolution of a yeast amyloid in vivo is shaped by chaperones

Cryo-electron microscopy (cryo-EM) studies of amyloid fibrils have revealed endpoint structures of disease-relevant filaments and polymorphic intermediates formed during in vitro assembly of prion-like proteins. However, how transmissible prion or prion-like amyloids evolve during de novo formation and maturation in living cells remains unknown. Here, using the yeast prion [PSI+] as a model, we isolated Sup35NM amyloid fibrils from successive stages of [PSI+] maturation in Saccharomyces cerevisiae and characterised their near-atomic structures and population-level structural diversity by combining cryo-EM and atomic force microscopy. We show that intermediate and mature states differ in predominant fibril structure and the regions of the Sup35 sequence incorporated into the core, and that structural diversity decreases during maturation. Curing of [PSI+] at the mature state by guanidine hydrochloride (GdnHCl), which selectively inhibits ATPase activity of the chaperone Hsp104, restored both the predominant intermediate amyloid structure and the broader structural diversity characteristic of the intermediate state. In addition, Hsp104, Ssa1 (Hsp70) and Sis1 (Hsp40) associate differently with fibrils from the two states. Together, these findings provide direct structural evidence for amyloid evolution in vivo and support a chaperone-mediated mechanism of conformer selection within a polymorphic amyloid population.

molecular biology↗

bioRxiv2025

A dividing cell model for stable propagation and curing of bona fide human sporadic Creutzfeldt-Jakob Disease prions

Prions are assemblies of misfolded proteins that cause transmissible, progressive neurodegenerative disease in humans and other mammals. Human prion diseases have particular public health and biological significance, both due to their transmissibility between hosts, and the mechanisms they share with many other neurodegenerative conditions. However, their study has been considerably impeded by the absence of a cell-based system capable of reproducibly propagating and quantifying bona fide human prion infectivity, which has been a goal for several decades. Here, we describe the first robust, cell-based assay of human prion infectivity in dividing cells. We found that CAD5 cells expressing human prion protein instead of the endogenous mouse prion protein, replicate human prion infectivity from brain samples of patients with sporadic Creutzfeldt-Jakob disease (sCJD) expressing valine at codon 129 of the prion protein gene. Moreover, these cells quantify human prion infectivity with similar sensitivity to the current gold standard animal bioassay, at a fraction of the cost and time, maintain persistent infection that can be cured with an anti-prion treatment, and can be adapted for therapeutic screening. This novel system permits direct cell-based quantification and investigation of human prion infectivity for the first time.

neuroscience↗

bioRxiv2025

Intracellular Trafficking SNARE Protein, Syntaxin-6, is a Modifier of Prion and Tau Pathogenesis in vivo and in Cellular Models

Syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk factor for sporadic prion disease, progressive supranuclear palsy and Alzheimers disease. However, no study has validated its functional role in these diseases, explored the disease stage at which it is acting nor its mechanism of action. Here, we show that syntaxin-6 acts at early stages of prion disease in experimental mice by increasing disease transmission risk following inoculation with low prion doses. Conversely, syntaxin-6 does not affect prion propagation kinetics or toxicity during established disease. Syntaxin-6 manipulation in cellular models profoundly alters the subcellular distribution and morphologies of disease-related PrP and modifies prion export. Furthermore, syntaxin-6 knockout in a transgenic tauopathy mouse model exerts protective effects on numerous physiological, behavioural and neuropathological outcome measures. Therefore, our studies firmly establish syntaxin-6 as a modifier of prion and tau pathogenesis, providing key insights into a fundamental mechanism of neurodegeneration.

neuroscience↗

bioRxiv2024

Induction and characterisation of Abeta and tau pathology in AppNL-F/NL-F mice following inoculation with Alzheimer's disease brain homogenate

Alzheimers disease (AD) is defined by the accumulation of neurofibrillary tangles containing hyperphosphorylated Tau and plaques containing Amyloid-{beta} (A{beta}). The aggregation of these two proteins is considered central to the disease. The lack of animal models that can recapitulate A{beta} and tau pathologies without overexpressing these proteins has hindered AD research. Accelerating pathology by inoculating A{beta} and tau seeds has helped to understand their prion-like propagation in the brain. Previous studies failed to characterise both A{beta} and tau pathologies in vivo upon inoculating AD brain homogenates. Here we present a longitudinal and systematic study; we inoculated the AppNL-F/NL-F knockin mice, which express humanised A{beta} and murine wild-type tau, with extracts from diseased human brains to analyse the contribution of A{beta} and tau assemblies to AD pathogenesis. We found that mice inoculated with AD brain extracts evinced early and prominent amyloid deposition, while those injected with control brain extracts or vehicle did not. Parenchymal and vascular amyloid accumulated in the same brain regions affected in control-inoculated AppNL-F/NL-F mice. However, the extent of vascular amyloid far exceeded that seen in AppNL-F/NL-Fmice injected with control brain extracts, and parenchymal deposits extended to a previously untargeted brain region - the cerebellum. An end-point titration of an AD brain homogenate in AppNL-F/NL-F mice demonstrated that human A{beta} seeds can be titrated in a prion-like fashion, which is useful for sample comparison, diagnostic and risk studies. Notably, the inoculation of AppNL-F/NL-F mice with AD brain homogenate induced intense tau phosphorylation, and provides more detailed context for the inoculation of AppNL-F/NL-F mice with human samples to study temporal and mechanistic relationships between A{beta} and tau pathology, vascular amyloid deposition and bioactivity of A{beta} seeds.

neuroscience↗

bioRxiv2023

Alanine replacements in the structured C-terminal domain of the prion protein reveal conformationally variable regions as major determinants for prion propagation

Mutational analysis of the cellular prion protein (PrPC) has revealed various regions of the protein that modulate prion propagation. However, most approaches involve deletions, insertions, or replacements in the presence of the wild-type cellular protein, which may mask the true phenotype. Here, site-directed alanine mutagenesis of PrPC was conducted to identify sites particularly a surface patch of the protein pertinent to prion propagation in the absence of the wild-type prion protein. Mutations were targeted to the helical, sheet and loop regions of PrPC, or a combination thereof and the mutated proteins expressed in PK1 cells in which endogenous PrPC had been silenced. PK1 cells are a clone of mouse neuroblastoma cells that are highly susceptible to Rocky Mountain Laboratory mouse prions. Using the scrapie cell assay, a highly sensitive cell culture-based bioassay for quantifying infectious titres of mouse prions, we found that all mutations within the structured 121-230 domain, irrespective of secondary structure, severely reduced prion propagation. The reduction was most pronounced for mutations within conformationally variable regions of the protein (G123A.L124A.G125A and V188A.T191A.T192A) and those neighbouring or within helix 1 (S134A.R135A.M153A and H139A.G141A.D146A). While mutations G123A and G125A would likely disrupt the structure of the prion fibril, the other mutations are unlikely to cause disruption. Our data therefore suggests that conformationally variable regions within the structured domain of PrPC are the major determinants of prion propagation efficacy.

biochemistry↗

bioRxiv2023

Knockout of Sporadic Creutzfeldt-Jakob Disease Risk Gene Stx6 in Mice Extends Prion Disease Incubation Time

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimers disease. Author SummarySporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is an invariably fatal disease with no established disease-modifying treatments. The identification of STX6 as a proposed risk gene for sCJD motivated the generation of a new mouse knockout model, in which we found no grossly deleterious phenotypes. A transmission study in Stx6-/-, Stx6+/- and Stx6+/+ mice challenged with two prion strains showed reduced syntaxin-6 expression is associated with a modest prolongation of prion disease incubation periods, supporting a pathological role of Stx6 expression in prion disease pathogenesis. Syntaxin-6 appears to have pleiotropic risk effects across multiple neurodegenerative diseases including progressive supranuclear palsy and Alzheimers disease. Thus, this work supports further exploration of the STX6 susceptibility mechanism, which likely has relevance across multiple neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Impact of cellular prion protein expression on disease progression and pathology in two mouse models of Alzheimer's disease

The aggregation of amyloid-{beta} (A{beta}) monomers increases their neurotoxicity, and these oligomeric species are thought to be central to the pathogenesis of Alzheimers disease. Unsurprisingly for such a complex disease, current Alzheimers disease mouse models fail to fully mimic the clinical disease in humans. Moreover, results obtained in a given mouse model are not always reproducible in a different model. Cellular prion protein (PrPC) is now an established receptor for A{beta} oligomers. However, different groups studying the A{beta}-PrPC interaction in vivo using a variety of mouse models have obtained contradictory results. Here we performed a longitudinal study in two commonly used AD mouse models using a range of biochemical, histological and behavioural techniques and found similar contradictory results and a possible explanation for the discrepancy. We propose that these two mouse models produce A{beta} oligomers with different conformations. Therefore, binding to PrPC and the subsequent activation of toxic signalling cascade will occur only when the A{beta} oligomer species with appropriate conformation are present. Hence, it is crucial to select the appropriate model producing the appropriate species of A{beta} oligomers to study specific aspects of {beta}-amyloidosis and its downstream pathways. Further conformational characterisation of A{beta} oligomers and their binding to PrPC is required to better understand A{beta} neurotoxicity.

neuroscience↗

bioRxiv2022

Population Structure and Migration in the Eastern Highlands of Papua New Guinea; a Region Impacted by the kuru Epidemic

Populations of the Eastern Highlands of Papua New Guinea (EHPNG, area 11,157 km2) lived in relative isolation from the rest of the world until the mid-20th century, and the region contains a wealth of linguistic and cultural diversity. Notably, several populations of EHPNG were devastated by an epidemic prion disease, kuru, which at its peak in the mid-twentieth century led to some villages being almost depleted of adult women. Until now, population genetic analyses to learn about genetic diversity, migration, admixture and the impact of the kuru epidemic have been restricted to a small number of variants or samples. Here, we present a population genetic analysis of the region based on genome-wide genotype data of 943 individuals from 21 linguistic groups and 68 villages in EHPNG, including 34 villages in the South Fore linguistic group, which the group most affected by kuru. We find a striking degree of genetic population structure in the relatively small region (average FST between linguistic groups 0.024; area similar to Jamaica). The genetic population structure correlates well with linguistic grouping, with some noticeable exceptions. Also, we find evidence of a series of discrete admixture events that appear to coincide with previously expected introduction dates and movement of the sweet potato in the region. Finally, we find signatures of more recent migration within the EHPNG region and observe a substantial excess of female migration into the heavily kuru-affected South Fore linguistic group (p=0.0017, Chi Squared Test), likely reflecting the sex-bias in incidence of kuru. These data provide an in-depth look at the population genetics of a region devastated by a prion disease epidemic and which was until recently relatively isolated from the rest of the world.

genetics↗

bioRxiv2022

Loss of the first β-strand of human prion protein generates an aggregation-competent partially "open" form

Prion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). The pathway of PrP misfolding is still unclear, though previous data indicate the presence of a structural core in cellular PrP (PrPC), whose cooperative unfolding presents a substantial energy barrier on the path to prion formation. PrP is a GPI-anchored membrane protein, and a number of studies suggest that membrane interactions play an important role in the conversion of PrPC to its disease-associated form, including a transmembrane form of PrP in which a highly conserved region (residues 110 - 136) spans the ER membrane. Insertion of this region results in the detachment of the PrPC first {beta}-strand from the structural core. The effect of this removal on the structure, stability and self-association of the folded domain of PrPC is determined here through a biophysical characterisation of a truncated form of PrPC lacking this region. Whilst markedly destabilised, NMR chemical shifts show that the truncated protein exhibits tertiary structure characteristic of a fully folded protein and retains its native secondary structure elements, including the second strand of the PrP {beta}-sheet, but with altered conformational flexibility in the {beta}2-2 loop and first -helix. The latter is destabilised relative to the other helical regions of the protein, with markedly increased solvent exposure. This truncated form of PrP fibrilises more readily than the native form of the protein. These data suggest a stepwise mechanism, in which a destabilised "open" form of PrPC may be a key intermediate in the refolding to the fibrillar, pathogenic form of the protein.

biophysics↗

bioRxiv2022

Single-nuclei transcriptomics of mammalian prion diseases identifies dynamic gene signatures shared between species

Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein (PrP). The most common human form of the disease, sporadic Creutzfeldt-Jakob disease (sCJD), typically presents as a rapidly progressive dementia and has no effective treatments. Prion diseases are transmissible to laboratory rodents affording unprecedented opportunities to understand neurodegeneration in its evolving stages. Murine models are especially useful in prion research as they develop bona fide prion disease and recapitulate all biochemical and neuropathological hallmarks of human prion disease. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. This is at least in part because confounding effects related to brain cellular heterogeneity have not been resolved. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.

neuroscience↗

bioRxiv2022

Direct Observation of Competing Prion Protein Fibril Populations with Distinct Structures and Kinetics

In prion diseases, fibrillar assemblies of misfolded prion protein (PrP) self-propagate by incorporating PrP monomers. Using total internal reflection and transient amyloid binding super-resolution microscopy, our study analyses elongation of single PrP fibrils to reveal polymorphic populations, featuring structural and dynamic heterogeneity similar to prion strains, which were previously hidden in ensemble measurements. PrP fibrils elongated along a preferred direction by an intermittent stop- and-go mechanism. Fibrils fell into three main populations, which each displayed distinct elongation mechanisms incorporating different monomer structures and which maintained their properties even under elongation conditions favouring a different fibril type. Elongation of RML and ME7 prion rods likewise exhibited unique kinetic features. The discovery of polymorphic fibril populations of amyloid and prions growing in competition suggests that prions may present as quasispecies of structural isomorphs and that the replication environment may tilt the balance between prion isomorphs and amyloid species. HighlightsO_LISynthetic prion fibril populations contain structurally distinct fibril types C_LIO_LIFibril types faithfully elongate by different mechanisms C_LIO_LIFibril types compete for substrate depending on environment C_LIO_LIFibril populations model quasi-species behavior of prion strains C_LI eTOCReplication of different prion strains causes distinct disease phenotypes. Sun et al. analyzed the growth of individual synthetic prion protein fibrils by super-resolution microscopy and found populations of structurally distinct fibril types, which grew in competition to each other as a quasi-species, recapitulating basic prion strain characteristics in vitro.

biophysics↗

bioRxiv2022

Prion propagation is dependent on key amino acids in Charge cluster 2 within the prion protein

Prions consist of assemblies of aberrantly folded cellular prion protein (PrPC) upon template-assisted conversion and propagation of disease-associated PrP. To dissect the N-terminal residues critical for efficient prion propagation, we generated a library of point, double, or triple alanine replacements within residues 23-111 of PrP, stably expressed them in cells silenced for endogenous mouse PrPC and challenged the reconstituted cells with four mouse prion strains. Amino acids (aa) 105-111 of Charge Cluster 2 (CC2), which is disordered in PrPC, were required for propagation of all four prion strains; other residues had no effect or exhibited strain-specific effects. Replacements in CC2, including aa105-111, dominantly inhibited prion propagation in the presence of endogenous wild type PrPC whilst other changes were not inhibitory. Single alanine replacements within aa105-111 identified leucine 108 and valine 111 or the cluster of lysine 105, threonine 106 and asparagine 107 as critical for prion propagation. These residues mediate specific ordering of CC2 in the prion fibrils from Rocky Mountain Laboratory (RML) and ME7 mouse prion strains.

molecular biology↗

bioRxiv2022

A structural basis for prion strain diversity

Recent cryo-EM studies of infectious, ex vivo, prion fibrils from hamster 263K and mouse RML prion strains revealed a comparable, parallel in-register intermolecular {beta}-sheet (PIRIBS) amyloid architecture. Rungs of the fibrils are composed of individual prion protein (PrP) monomers that fold to create distinct N- and C-terminal lobes. However, disparity in the hamster/mouse PrP sequence precludes understanding how divergent prion strains emerge from an identical PrP substrate. Here, we determined the near-atomic resolution cryo-EM structure of infectious, ex vivo mouse prion fibrils from the ME7 prion strain and have compared this with the RML fibril structure. This structural comparison of two biologically distinct mouse-adapted prion strains suggests defined folding sub-domains of PrP rungs and the way in which they are interrelated, providing the first structural definition of intra-species prion strain-specific conformations.

biochemistry↗

bioRxiv2021

Mapping prion pathology in mice using quantitative imaging: an MRI study

Human prion diseases are fatal neurodegenerative disorders which cause cognitive impairment and neurological deficits. Additional measures of tissue status are necessary for improving the sensitivity and specificity of clinical diagnosis as in many cases clinical forms of prion disease are commonly mistaken for other forms of dementia. To that effect, we developed a set of quantitative magnetic resonance-based tools, including magnetic resonance spectroscopy (MRS), magnetization transfer ratio (MTR) and quantitative T1 and T2 imaging to study the course of the disease in an animal model of prion disease. Using in vivo MTR, significant changes were detected in the cortex and thalamus of late-stage prion -infected mice as compared to littermates. In addition, we found a significant increase of MTR in thalamus and cortex of 80 dpi healthy mice when compared with 160 dpi healthy mice suggestive of changes occurring during the development of the brain. Using quantitative T2 mapping, significantly higher values were measured in thalamus of prion mice at all stages of the disease (T2=40ms) while T1 was found to be significantly higher in cortex (T1=1.89s) and hippocampus, albeit only in late-stage prion mice as compared to aged-matched controls (T1=1.67s). Using quantitative MRS significant changes were detected in glutamate (Glu) and myo-inositol (Ins) at all stages of prion disease when compared with the control group. NAA, Cr, Lactate and Lipids were only found to be significantly different at early and late stages of the disease while Taurine (Tau) was only significantly increased in the asymptomatic stage without any significant change at early and late stages of the disease. These changes in MRI and MRS signals, which precede clinical signs of disease, could provide insights into the pathogenesis of this disease and may enable early detection of pathology.

biophysics↗

bioRxiv2021

Can Chemical Exchange Saturation Transfer (CEST MRI) be used as biomarker of disease progression in Prion Disease?

Human prion diseases are fatal neurodegenerative disorders that may have prolonged asymptomatic incubation periods. However, the underlying mechanism by which prions cause brain damage remains unclear. In turn, characterization of early pathological aspects would be of benefit for the diagnosis and potential treatment of these progressive neurodegenerative disorders. We investigated chemical exchange saturation transfer (CEST) MRI based on its exquisite sensitivity to cytosol protein content as a surrogate for prion disease pathology. Three groups of prion-infected mice at different stages of the disease underwent conventional magnetic resonance imaging and CEST MRI at 9.4T. For each mouse, chemical exchange contrasts were measured by applying five RF powers at various frequency offsets using magnetization transfer asymmetries. Relayed Nuclear Overhauser effects (NOE*) and amide proton transfer (APT*) were also assessed. For comparison, CEST MRI measurements were also made in healthy control mice brains. Here we show that alterations in CEST signal were detected before structural modifications or any clinical signs of prion disease. The detected CEST signal displayed different patterns at different stages of the disease indicating its potential for use as a longitudinal marker of disease progression. Highly significant correlations were found between CEST metrics and histopathological findings. A decline in NOE signal was positively correlated with abnormal prion protein deposition (R2 = 0.91) in the thalami of prion infected mice. Moreover, the NOE signal was negatively correlated with astrogliosis (R2 = 0.71) in the thalamus. No significant correlations were detected between NOE signals and spongiosis. MTR asymmetry at 3.5 ppm was also correlated with astrogliosis (R2 = 0.59), and prion protein deposition (R2 = 0.63) in thalamus. No significant changes were detected in APT* between prion-infected and control mice at all stages of the disease. Finally, MTR asymmetry between 2.8 and 3.2 ppm was correlated with prion protein deposition (R2 = 0.47) in the thalamus of prion -infected mice. To conclude, CEST MRI has potential utility as a biomarker of neurodegenerative processes in prion disease.

biophysics↗

bioRxiv2021

2.7 A cryo-EM structure of ex vivo RML prion fibrils

Mammalian prions are lethal infectious agents that propagate as distinct strains and are composed of multichain assemblies of misfolded host-encoded prion protein (PrP), often referred to as prion rods. The structural features that define infectious prion rods and the molecular determinants of prion strain diversity are poorly understood. Here, we present a near-atomic resolution cryo-EM structure of PrP fibrils present in highly infectious prion rod preparations isolated from the brains of RML prion-infected mice. We found that prion rods comprise single-protofilament helical amyloid fibrils that coexist with twisted pairs of the same protofilaments. Each rung of the protofilament is formed by a single PrP monomer with the ordered core comprising PrP residues 94-225, which folds to create two asymmetric lobes with the N-linked glycans and the glycosylphosphatidylinositol anchor projecting from the C-terminal lobe. The overall architecture is comparable to that of recently reported PrP fibrils isolated from the brain of hamsters infected with the 263K prion strain. However, there are marked conformational variations that could result from differences in PrP primary sequence and/or represent distinguishing features of the distinct prion strains. These conformational changes impact the overall geometry of the fibrils and may also impact fibril pairing, one or both of which may critically influence PrP glycoform selection that occurs during strain-specific prion propagation.

biochemistry↗

bioRxiv2020

Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium

Alpha-synuclein (-syn) fibrils, a major constituent of the neurotoxic Lewy Bodies in Parkinsons disease, form via nucleation dependent polymerization and can replicate by a seeding mechanism. Brazilin, a small molecule derived from red cedarwood trees in Brazil, has been shown to inhibit the fibrillogenesis of amyloid-beta (A{beta}) and -syn, prompting our inquiry in its mechanism of action. Here we test the effects of Brazilin on both seeded and unseeded -syn fibril formation and show that the natural polyphenol inhibits fibrillogenesis of -syn by a unique mechanism that is distinct from other polyphenols and is also distinct from its effect on A{beta}. Brazilin preserves the natively unfolded state of -syn by stabilizing the compact conformation of the -syn monomer over the aggregation-competent extended conformation. Molecular docking of Brazilin shows the molecule to interact both with unfolded -syn monomers and with the cross-{beta} sheet structure of -syn fibrils. Brazilin eliminates seeding competence of -syn assemblies from Parkinsons disease patient brain tissue, and treatment of pre-formed fibril assemblies with Brazilin significantly reduces their toxicity in primary neurons. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinsons Disease. Highlights- The natural polyphenol Brazilin binds to monomeric, oligomeric and fibrillar -syn - Brazilin shifts the equilibrium away from aggregation-competent monomer conformations - Brazilin inactivates seeding-competent -syn isolated from Parkinson patients brains - Brazilin detoxifies -syn aggregation intermediates and stabilizes mature amyloid fibrils Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=117 HEIGHT=200 SRC="FIGDIR/small/318220v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@447629org.highwire.dtl.DTLVardef@a9871dorg.highwire.dtl.DTLVardef@1e5a83dorg.highwire.dtl.DTLVardef@8843eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗