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Conformational fingerprinting of tau variants and strains by Raman spectroscopy

Conformational fingerprinting of tau variants and strains by Raman spectroscopy
Conformational fingerprinting of tau variants and strains by Raman spectroscopy
Tauopathies are a group of disorders in which the deposition of abnormally folded tau protein accompanies neurodegeneration. The development of methods for detection and classification of pathological changes in protein conformation are desirable for understanding the factors that influence the structural polymorphism of aggregates in tauopathies. We have previously demonstrated the utility of Raman spectroscopy for the characterization and discrimination of different protein aggregates, including tau, based on their unique conformational signatures. Building on this, in the present study, we assess the utility of Raman spectroscopy for characterizing and distinguishing different conformers of the same protein which in the case of tau are unique tau strains generated in vitro. We now investigate the impact of aggregation environment, cofactors, post-translational modification and primary sequence on the Raman fingerprint of tau fibrils. Using quantitative conformational fingerprinting and multivariate statistical analysis, we found that the aggregation of tau in different buffer conditions resulted in the formation of distinct fibril strains. Unique spectral markers were identified for tau fibrils generated using heparin or RNA cofactors, as well as for phosphorylated tau. We also determined that the primary sequence of the tau monomer influenced the conformational signature of the resulting tau fibril, including 2N4R, 0N3R, K18 and P301S tau variants. These results highlight the conformational polymorphism of tau fibrils, which is reflected in the wide range of associated neurological disorders. Furthermore, the analyses presented in this study provide a benchmark for the Raman spectroscopic characterization of tau strains, which may shed light on how the aggregation environment, cofactors and post-translational modifications influence tau conformation in vivo in future studies.
2046-2069
8899-8915
Devitt, George
088c46c0-9dcf-4c83-acfd-16c6c9d0ca88
Crisford, Anna
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Rice, William
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Weismiller, Hilary A.
d2979e07-e0f4-4538-b1e2-658798c19bd1
Fan, Zhanyun
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Commins, Caitlin
b842abf5-4694-4fcd-b3e9-da73f27b7eef
Hyman, Bradley T.
66879b74-78be-41cd-870a-64508b55e470
Margittai, Martin
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Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Devitt, George
088c46c0-9dcf-4c83-acfd-16c6c9d0ca88
Crisford, Anna
135675e1-a172-4d93-989b-93d1efb022c3
Rice, William
fd89eaff-f143-49f5-9078-d66d83f9c8b5
Weismiller, Hilary A.
d2979e07-e0f4-4538-b1e2-658798c19bd1
Fan, Zhanyun
3cd37d68-0f84-4539-bdc9-81f4eb4c6a23
Commins, Caitlin
b842abf5-4694-4fcd-b3e9-da73f27b7eef
Hyman, Bradley T.
66879b74-78be-41cd-870a-64508b55e470
Margittai, Martin
00a40395-fb73-4187-b878-a7089c5e1744
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119

Devitt, George, Crisford, Anna, Rice, William, Weismiller, Hilary A., Fan, Zhanyun, Commins, Caitlin, Hyman, Bradley T., Margittai, Martin, Mahajan, Sumeet and Mudher, Amritpal (2021) Conformational fingerprinting of tau variants and strains by Raman spectroscopy. RSC Advances, 11 (15), 8899-8915. (doi:10.1039/d1ra00870f).

Record type: Article

Abstract

Tauopathies are a group of disorders in which the deposition of abnormally folded tau protein accompanies neurodegeneration. The development of methods for detection and classification of pathological changes in protein conformation are desirable for understanding the factors that influence the structural polymorphism of aggregates in tauopathies. We have previously demonstrated the utility of Raman spectroscopy for the characterization and discrimination of different protein aggregates, including tau, based on their unique conformational signatures. Building on this, in the present study, we assess the utility of Raman spectroscopy for characterizing and distinguishing different conformers of the same protein which in the case of tau are unique tau strains generated in vitro. We now investigate the impact of aggregation environment, cofactors, post-translational modification and primary sequence on the Raman fingerprint of tau fibrils. Using quantitative conformational fingerprinting and multivariate statistical analysis, we found that the aggregation of tau in different buffer conditions resulted in the formation of distinct fibril strains. Unique spectral markers were identified for tau fibrils generated using heparin or RNA cofactors, as well as for phosphorylated tau. We also determined that the primary sequence of the tau monomer influenced the conformational signature of the resulting tau fibril, including 2N4R, 0N3R, K18 and P301S tau variants. These results highlight the conformational polymorphism of tau fibrils, which is reflected in the wide range of associated neurological disorders. Furthermore, the analyses presented in this study provide a benchmark for the Raman spectroscopic characterization of tau strains, which may shed light on how the aggregation environment, cofactors and post-translational modifications influence tau conformation in vivo in future studies.

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Accepted/In Press date: 18 February 2021
Published date: 26 February 2021

Identifiers

Local EPrints ID: 447276
URI: http://eprints.soton.ac.uk/id/eprint/447276
ISSN: 2046-2069
PURE UUID: bc13d972-8840-4c18-a81f-07d7730ccb32
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 Sumeet Mahajan: ORCID iD orcid.org/0000-0001-8923-6666

Catalogue record

Date deposited: 08 Mar 2021 17:31
Last modified: 26 Nov 2021 03:21

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Contributors

Author: George Devitt ORCID iD
Author: Anna Crisford ORCID iD
Author: William Rice
Author: Hilary A. Weismiller
Author: Zhanyun Fan
Author: Caitlin Commins
Author: Bradley T. Hyman
Author: Martin Margittai
Author: Sumeet Mahajan ORCID iD
Author: Amritpal Mudher

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