Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

Martin Nors Pedersen; Vito Foderà; Istvan Horvath; Andreas van Maarschalkerweerd; Katrine Nørgaard Toft; Christoph Weise; Fredrik Almqvist; Magnus Wolf-Watz; Pernilla Wittung-Stafshede; Bente Vestergaard

doi:10.1038/srep10422

Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

Martin Nors Pedersen, Vito Foderà, Istvan Horvath, Andreas van Maarschalkerweerd, Katrine Nørgaard Toft, Christoph Weise, Fredrik Almqvist, Magnus Wolf-Watz, Pernilla Wittung-Stafshede, Bente Vestergaard

21 Citationer (Scopus)

Abstract

Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an ‘oligomer stacking model’ for alpha-synuclein fibril elongation.

Originalsprog	Engelsk
Artikelnummer	10422
Tidsskrift	Scientific Reports
Vol/bind	5
Sider (fra-til)	1-12
Antal sider	12
ISSN	2045-2322
DOI	https://doi.org/10.1038/srep10422
Status	Udgivet - 28 maj 2015

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10.1038/srep10422Licens: CC BY

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title = "Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth",

abstract = "Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer' s and Parkinson' s disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha-synuclein fibril elongation.",

keywords = "Alzheimer Disease, Amyloid, Amyloidogenic Proteins, Humans, Ligands, Parkinson Disease, Protein Aggregation, Pathological, Protein Structure, Secondary, Pyridones, alpha-Synuclein",

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T1 - Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

AU - Pedersen, Martin Nors

AU - Foderà, Vito

AU - Horvath, Istvan

AU - van Maarschalkerweerd, Andreas

AU - Nørgaard Toft, Katrine

AU - Weise, Christoph

AU - Almqvist, Fredrik

AU - Wolf-Watz, Magnus

AU - Wittung-Stafshede, Pernilla

AU - Vestergaard, Bente

PY - 2015/5/28

Y1 - 2015/5/28

N2 - Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer' s and Parkinson' s disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha-synuclein fibril elongation.

AB - Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer' s and Parkinson' s disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha-synuclein fibril elongation.

KW - Alzheimer Disease

KW - Amyloid

KW - Amyloidogenic Proteins

KW - Humans

KW - Ligands

KW - Parkinson Disease

KW - Protein Aggregation, Pathological

KW - Protein Structure, Secondary

KW - Pyridones

KW - alpha-Synuclein

U2 - 10.1038/srep10422

DO - 10.1038/srep10422

M3 - Journal article

C2 - 26020724

SN - 2045-2322

VL - 5

SP - 1

EP - 12

JO - Scientific Reports

JF - Scientific Reports

M1 - 10422

ER -

Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

Abstract

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