Aggregation and Amyloid Fibril Formation Induced by Chemical Dimerization of Recombinant Prion Protein in Physiological-like Conditions

Roostaee, Alireza; Côté, Sébastien; Roucou, Xavier

doi:10.1074/jbc.m109.057950

Cited by 29 publications

(28 citation statements)

References 54 publications

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“…Homodimer formation has been characterized as an essential factor in the aggregation pathway of numerous proteins, such as serpin, tau, and prion protein which are all involved in protein misfolding disorders [14,25,26]. In this regard, in vitro experiments have reported the existence of a dimeric state during conversion of α-Syn from soluble monomers to oligomeric species [27].…”

Section: Introductionmentioning

confidence: 99%

Aggregation and neurotoxicity of recombinant α-synuclein aggregates initiated by dimerization

Roostaee

Beaudoin

Staskevicius

et al. 2013

Mol Neurodegeneration

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BackgroundAggregation of the α-Synuclein (α-Syn) protein, amyloid fibril formation and progressive neurodegeneration are the neuropathological hallmarks of Parkinson's Disease (PD). However, a detailed mechanism of α-Syn aggregation/fibrillogenesis and the exact nature of toxic oligomeric species produced during amyloid formation process are still unknown.ResultsIn this study, the rates of α-Syn aggregation were compared for the recombinant wild-type (WT) α-Syn and a structurally relevant chimeric homologous protein containing an inducible Fv dimerizing domain (α-SynFv), capable to form dimers in the presence of a divalent ligand (AP20187). In the presence of AP20187, we report a rapid random coil into β-sheet conformational transformation of α-SynFv within 24 h, whereas WT α-Syn showed 24 h delay to achieve β-sheet structure after 48 h. Fluorescence ANS and ThT binding experiments demonstrate an accelerated oligomer/amyloid formation of dimerized α-SynFv, compared to the slower oligomerization and amyloidogenesis of WT α-Syn or α-SynFv without dimerizer AP20187. Both α-SynFv and α-Syn pre-fibrillar aggregates internalized cells and induced neurotoxicity when injected into the hippocampus of wild-type mice. These recombinant toxic aggregates further converted into non-toxic amyloids which were successfully amplified by protein misfolding cyclic amplification method, providing the first evidence for the in vitro propagation of synthetic α-Syn aggregates.ConclusionsTogether, we show that dimerization is important for α-Syn conformational transition and aggregation. In addition, α-Syn dimerization can accelerate the formation of neurotoxic aggregates and amyloid fibrils which can be amplified in vitro. A detailed characterization of the mechanism of α-Syn aggregation/amyloidogenesis and toxicity is crucial to comprehend Parkinson's disease pathology at the molecular level.

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Section: Introductionmentioning

confidence: 99%

Aggregation and neurotoxicity of recombinant α-synuclein aggregates initiated by dimerization

Roostaee

Beaudoin

Staskevicius

et al. 2013

Mol Neurodegeneration

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“…There is no doubt that more advanced machine learning approaches, such as support vector machines, neuron networks and decision trees [21,22], would allow to combine the identified features and others to further characterise chameleon interfaces. Since, many chameleon fragments have been associated to human diseases through aggregation [4,7,17], the ability to detect a specific class of chameleon fragments, i.e. those able to form symmetric homodimer β-sheet interfaces, should contribute, not only, to a better insight about homodimerisation, but also in aggregation mechanisms.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to mutations, a protein's environment may also affect its secondary structure. For example, it has been shown that the prion protein, PrP C , changes its conformation and forms aggregates when interacting with one of its isoforms PrP SC [17]. Those β-sheet aggregates are called amyloid fibrils [4] and have been linked to several human diseases including Alzheimer's, Parkinson's and Creutzfeldt-Jakob's [7].…”

Section: Introductionmentioning

confidence: 98%

Data Mining the Protein Data Bank to Identify and Characterise Chameleon Coil Sequences that Form Symmetric Homodimer β-Sheet Interfaces

Laibe

Broutin

Caffrey

et al. 2017

Bioinformatics and Biomedical Engineering

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Abstract.A protein's environment may affect its secondary structure. In this study, the focus is on homodimers with symmetric β-sheet interfaces resulting from the conversion of coil sequences into β-strands. All homodimers in the Protein Data Bank relying on those chameleon sequences have been identified. Initial analysis based on sequential and structural features has revealed that many of those dimers display specific properties which could contribute to their detection. Such result is important since it could provide some insight on dimerisation and possibly aggregation mechanisms.

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“…87 A model for conversion of PrP C to amyloid based on dimeric domainswapping has been proposed, 88 inspired by the domain-swapped dimer found in the crystal structure of human PrP. 78 Most interestingly, synthetic PrP dimers were toxic to neurons both in culture 89,90 and in mouse models of prion disease, 90 and antibodies raised against tandem dimers of PrP showed anti-prion activity in vivo. 91 More recently, it was found that recombinant PrP could be converted into a toxic dimer using PMCA.…”

Section: Relevance Of the Misfolded Dimer To Prion Diseasementioning

confidence: 98%

Comparing the energy landscapes for native folding and aggregation of PrP

Dee

Woodside

2016

Prion

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Protein sequences are evolved to encode generally one folded structure, out of a nearly infinite array of possible folds. Underlying this code is a funneled free energy landscape that guides folding to the native conformation. Protein misfolding and aggregation are also a manifestation of free-energy landscapes. The detailed mechanisms of these processes are poorly understood, but often involve rare, transient species and a variety of different pathways. The inherent complexity of misfolding has hampered efforts to measure aggregation pathways and the underlying energy landscape, especially using traditional methods where ensemble averaging obscures important rare and transient events. We recently studied the misfolding and aggregation of prion protein by examining 2 monomers tethered in close proximity as a dimer, showing how the steps leading to the formation of a stable aggregated state can be resolved in the single-molecule limit and the underlying energy landscape thereby reconstructed. This approach allows a more quantitative comparison of native folding versus misfolding, including fundamental differences in the dynamics for misfolding. By identifying key steps and interactions leading to misfolding, it should help to identify potential drug targets. Here we describe the importance of characterizing free-energy landscapes for aggregation and the challenges involved in doing so, and we discuss how single-molecule studies can help test proposed structural models for PrP aggregates.

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Aggregation and Amyloid Fibril Formation Induced by Chemical Dimerization of Recombinant Prion Protein in Physiological-like Conditions

Cited by 29 publications

References 54 publications

Aggregation and neurotoxicity of recombinant α-synuclein aggregates initiated by dimerization

Aggregation and neurotoxicity of recombinant α-synuclein aggregates initiated by dimerization

Data Mining the Protein Data Bank to Identify and Characterise Chameleon Coil Sequences that Form Symmetric Homodimer β-Sheet Interfaces

Comparing the energy landscapes for native folding and aggregation of PrP

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