The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β1−40 peptide

Narayan, Priyanka; Orte, Ángel; Clarke, R.N.; Bolognesi, Benedetta; Hook, Sharon; Ganzinger, Kristina A.; Meehan, Sarah; Wilson, Mark R.; Dobson, Christopher M.; Klenerman, David

doi:10.1038/nsmb.2191

Cited by 244 publications

(335 citation statements)

References 45 publications

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“…CD2AP is an adaptor molecule involved in dynamic actin remodeling and membrane trafficking, and CLU encodes clusterin, which is a molecular chaperone,39 is present in senile plaques, and has been shown to modulate Aβ oligomer assembly 40. We previously reported rare SNPs and small structural variants within the CLU gene that were associated with LOAD 41…”

Section: Discussionmentioning

confidence: 99%

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Vardarajan

Ghani

Kahn

et al. 2015

Annals of Neurology

135

117

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ObjectiveTo detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).MethodsWe conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.ResultsOverall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.InterpretationTargeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498

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Section: Discussionmentioning

confidence: 99%

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Vardarajan

Ghani

Kahn

et al. 2015

Annals of Neurology

135

117

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“…Because oligomeric species formed under such conditions consist predominantly of non-β-structures, it is interesting to speculate that nature might have evolved a portfolio of chaperones to target specifically both the non-β-as well as the conventional β-aggregated forms to curtail pathological aggregation. Recent evidence suggests that such a situation might, indeed, occur for extracellular chaperones (70,71). Although these simulations focused on the Aβ1-42 peptide, we expect aspects of the mechanism proposed here to be applicable to other amyloid proteins, such as the prion protein or α-synuclein.…”

Section: Discussionmentioning

confidence: 99%

Crucial role of nonspecific interactions in amyloid nucleation

Šarić

Chebaro

Knowles

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

173

172

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Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical onestep nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the β-sheet-rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory.amyloid | protein aggregation | protein oligomers | neurodegeneration | coarse-grained simulations D uring the process of amyloid formation, normally soluble proteins assemble into fibrils that are enriched in β-sheet content and have diameters of a few nanometers and lengths up to several micrometers. This phenomenon has been implicated in a variety of pathogenic processes, including Alzheimer's and Parkinson's diseases, type 2 diabetes, and systemic amyloidoses (1-3). The association with human diseases has largely motivated a long-standing effort to probe the assembly process, and numerous studies have aimed at elucidating the mechanism of amyloid aggregation (4). The basic nature of the aggregation reaction has emerged as a nucleation and growth process (5, 6), where the aggregates are created through a not well-understood primary nucleation event and can grow by recruiting additional peptides or proteins to their ends (7,8). In this paper, we focus on the nature of this primary step in amyloid nucleation and the fundamental initial events that underlie amyloid formation.Amyloidogenic peptides and proteins, when in their nonpathological cellular form, can range in the structures from mainly α-helical to β-sheet and even random coil, whereas the amyloid forms of proteins possess a generic cross-β-structure ...

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“…Indeed, the concomitant inhibition of oligomer toxicity and increased oligomer size induced by chaperones, via recruitment of more misfolded protein oligomers into the aggregates, has been interpreted to mean that chaperoneinduced clustering of oligomers is a strategy used by chaperones to inhibit oligomer toxicity (Ojha et al, 2011;Mannini et al, 2012, Binger et al, 2013Cascella et al, 2013a). By contrast, using single-molecule fluorescence techniques, it has been shown that clusterin and Bc are able to bind preformed oligomers of A and sequester them from dissociation or further growth into fibrils, revealing another possible mechanism of action of molecular chaperones which is binding in the absence of aggregate clustering (Narayan et al, 2011;Narayan et al, 2012). In the case of Clu, the formation of complexes with misfolded proteins is thought to be relevant in the in vivo clearance of these aberrant species via membrane-associated receptors, such as the LRP-2 receptor (Hammand et al, 1997;Cole and Ard, 2000;Bartl et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Cappelli

Penco²,

Mannini³

et al. 2016

Biological Chemistry

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. (2016). Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations. Biological Chemistry: official scientific journal of the GBM, 397 (5), 401-415. Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations AbstractLiving systems protect themselves from aberrant proteins by a network of chaperones. We have tested in vitro the effects of different concentrations, ranging from 0 to 16 μm, of two molecular chaperones, namely αB-crystallin and clusterin, and an engineered monomeric variant of transthyretin (M-TTR), on the morphology and cytotoxicity of preformed toxic oligomers of HypF-N, which represent a useful model of misfolded protein aggregates. Using atomic force microscopy imaging and static light scattering analysis, all were found to bind HypF-N oligomers and increase the size of the aggregates, to an extent that correlates with chaperone concentration. SDS-PAGE profiles have shown that the large aggregates were predominantly composed of the HypF-N protein. ANS fluorescence measurements show that the chaperone-induced clustering of HypF-N oligomers does not change the overall solvent exposure of hydrophobic residues on the surface of the oligomers. αB-crystallin, clusterin and M-TTR can diminish the cytotoxic effects of the HypF-N oligomers at all chaperone concentration, as demonstrated by MTT reduction and Ca2+ influx measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasizes the efficiency and versatility of these protein molecules. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsCappelli, S., Penco, A., Mannini, B., Cascella, R., Wilson, M. R., Ecroyd, H., Li, X., Buxbaum, J. N., Dobson, C. M., Cecchi, C., Relini, A. & Chiti, F. (2016 measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasises the efficiency and versatility of these protein molecules.

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The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β1−40 peptide

Cited by 244 publications

References 45 publications

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Crucial role of nonspecific interactions in amyloid nucleation

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

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