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Conformational evolution of molecular signatures during Amyloi-dogenic protein aggregation

Conformational evolution of molecular signatures during Amyloi-dogenic protein aggregation
Conformational evolution of molecular signatures during Amyloi-dogenic protein aggregation
Aggregation is a pathological hallmark of proteinopathies such as Alzheimer’s disease and results in the deposition of β-sheet-rich amyloidogenic protein aggregates. Such proteinopathies can be classified by the identity of one or more aggregated protein, with recent evidence also suggesting that distinct molecular conformers (strains) of the same protein can be observed in different diseases, as well is in sub-types of the same disease. Therefore, methods for the quantification of pathological changes in protein conformation are central to understanding and treating proteinopathies. In this work the evolution of Raman spectroscopic molecular signatures of three conformationally distinct proteins, Bovine Serum Albumin (α-helical-rich), β2-microglobulin (β-sheet-rich) and tau (natively disordered), was assessed during aggregation into oligomers and fibrils. The morphological evolution was tracked using Atomic Force Microscopy and corresponding conformational changes were assessed by their Raman signatures acquired in both wet and dried conditions. A deconvolution model was developed which allowed us to quantify the conformation of the non-regular protein tau, as well as for the oligomeric and fibrillar species of each of the proteins. Principle component analysis of the fingerprint region allowed further identification of the distinguishing spectral features and unsupervised distinction. While an increase in β-sheet is seen on aggregation, crucially, however, each protein also retains a significant proportion of its native monomeric structure after aggregation. Thus, spectral analysis of each aggregated species, oligomeric, as well as fibrillar, for each protein resulted in a unique and quantitative ‘conformational fingerprint’. This approach allowed us to provide the first differential detection of both oligomers and fibrils of the three different amyloidogenic proteins, including tau, whose aggregates have never before been interrogated using spontaneous Raman spectroscopy. Quantitative ‘conformational fingerprinting’ by Raman spectroscopy thus demonstrates its huge potential and utility in understanding proteinopathic disease mechanisms and for providing strain-specific early diagnostic markers and targets for disease-modifying therapies.
1948-7193
4593-4611
Devitt, George
088c46c0-9dcf-4c83-acfd-16c6c9d0ca88
Rice, William
4b3ca32c-1602-45b3-971f-6683e5c8e6db
Crisford, Anna
135675e1-a172-4d93-989b-93d1efb022c3
Nandhakumar, Iris S.
e9850fe5-1152-4df8-8a26-ed44b5564b04
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Devitt, George
088c46c0-9dcf-4c83-acfd-16c6c9d0ca88
Rice, William
4b3ca32c-1602-45b3-971f-6683e5c8e6db
Crisford, Anna
135675e1-a172-4d93-989b-93d1efb022c3
Nandhakumar, Iris S.
e9850fe5-1152-4df8-8a26-ed44b5564b04
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9

Devitt, George, Rice, William, Crisford, Anna, Nandhakumar, Iris S., Mudher, Amritpal and Mahajan, Sumeet (2019) Conformational evolution of molecular signatures during Amyloi-dogenic protein aggregation. ACS Chemical Neuroscience, 10 (11), 4593-4611. (doi:10.1021/acschemneuro.9b00451).

Record type: Article

Abstract

Aggregation is a pathological hallmark of proteinopathies such as Alzheimer’s disease and results in the deposition of β-sheet-rich amyloidogenic protein aggregates. Such proteinopathies can be classified by the identity of one or more aggregated protein, with recent evidence also suggesting that distinct molecular conformers (strains) of the same protein can be observed in different diseases, as well is in sub-types of the same disease. Therefore, methods for the quantification of pathological changes in protein conformation are central to understanding and treating proteinopathies. In this work the evolution of Raman spectroscopic molecular signatures of three conformationally distinct proteins, Bovine Serum Albumin (α-helical-rich), β2-microglobulin (β-sheet-rich) and tau (natively disordered), was assessed during aggregation into oligomers and fibrils. The morphological evolution was tracked using Atomic Force Microscopy and corresponding conformational changes were assessed by their Raman signatures acquired in both wet and dried conditions. A deconvolution model was developed which allowed us to quantify the conformation of the non-regular protein tau, as well as for the oligomeric and fibrillar species of each of the proteins. Principle component analysis of the fingerprint region allowed further identification of the distinguishing spectral features and unsupervised distinction. While an increase in β-sheet is seen on aggregation, crucially, however, each protein also retains a significant proportion of its native monomeric structure after aggregation. Thus, spectral analysis of each aggregated species, oligomeric, as well as fibrillar, for each protein resulted in a unique and quantitative ‘conformational fingerprint’. This approach allowed us to provide the first differential detection of both oligomers and fibrils of the three different amyloidogenic proteins, including tau, whose aggregates have never before been interrogated using spontaneous Raman spectroscopy. Quantitative ‘conformational fingerprinting’ by Raman spectroscopy thus demonstrates its huge potential and utility in understanding proteinopathic disease mechanisms and for providing strain-specific early diagnostic markers and targets for disease-modifying therapies.

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Accepted/In Press date: 6 September 2019
e-pub ahead of print date: 29 October 2019
Published date: 20 November 2019

Identifiers

Local EPrints ID: 434788
URI: http://eprints.soton.ac.uk/id/eprint/434788
ISSN: 1948-7193
PURE UUID: 918f9e7c-ee6c-4b27-9f06-64334c7089b0
ORCID for George Devitt: ORCID iD orcid.org/0000-0001-7179-4459
ORCID for Anna Crisford: ORCID iD orcid.org/0000-0001-5775-643X
ORCID for Iris S. Nandhakumar: ORCID iD orcid.org/0000-0002-9668-9126
ORCID for Sumeet Mahajan: ORCID iD orcid.org/0000-0001-8923-6666

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Date deposited: 09 Oct 2019 16:30
Last modified: 26 Nov 2021 05:53

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Contributors

Author: George Devitt ORCID iD
Author: William Rice
Author: Anna Crisford ORCID iD
Author: Amritpal Mudher
Author: Sumeet Mahajan ORCID iD

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