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Conformational fingerprinting with Raman spectroscopy reveals protein structure as a translational biomarker of muscle pathology

Lookup NU author(s): Professor Grainne Gorman, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

© 2024 The Royal Society of Chemistry.Neuromuscular disorders are a group of conditions that can result in weakness of skeletal muscles. Examples include fatal diseases such as amyotrophic lateral sclerosis and conditions associated with high morbidity such as myopathies (muscle diseases). Many of these disorders are known to have abnormal protein folding and protein aggregates. Thus, easy to apply methods for the detection of such changes may prove useful diagnostic biomarkers. Raman spectroscopy has shown early promise in the detection of muscle pathology in neuromuscular disorders and is well suited to characterising the conformational profiles relating to protein secondary structure. In this work, we assess if Raman spectroscopy can detect differences in protein structure in muscle in the setting of neuromuscular disease. We utilise in vivo Raman spectroscopy measurements from preclinical models of amyotrophic lateral sclerosis and the myopathy Duchenne muscular dystrophy, together with ex vivo measurements of human muscle samples from individuals with and without myopathy. Using quantitative conformation profiling and matrix factorisation we demonstrate that quantitative ‘conformational fingerprinting’ can be used to identify changes in protein folding in muscle. Notably, myopathic conditions in both preclinical models and human samples manifested a significant reduction in α-helix structures, with concomitant increases in β-sheet and, to a lesser extent, nonregular configurations. Spectral patterns derived through non-negative matrix factorisation were able to identify myopathy with a high accuracy (79% in mouse, 78% in human tissue). This work demonstrates the potential of conformational fingerprinting as an interpretable biomarker for neuromuscular disorders.


Publication metadata

Author(s): Alix JJP, Plesia M, Dudgeon AP, Kendall CA, Hewamadduma C, Hadjivassiliou M, Gorman GS, Taylor RW, McDermott CJ, Shaw PJ, Mead RJ, Day JC

Publication type: Article

Publication status: Published

Journal: Analyst

Year: 2024

Volume: 149

Issue: 9

Pages: 2738-2746

Print publication date: 07/05/2024

Online publication date: 27/03/2024

Acceptance date: 11/03/2024

Date deposited: 14/05/2024

ISSN (print): 0003-2654

ISSN (electronic): 1364-5528

Publisher: Royal Society of Chemistry

URL: https://doi.org/10.1039/d4an00320a

DOI: 10.1039/d4an00320a

PubMed id: 38533726


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Funding

Funder referenceFunder name
203105/Z/16/ZWellcome Trust
G0800674
Lily Foundation
Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease
Mito Foundation
Mitochondrial Disease Patient Cohort (UK)
MR/S005021/1Medical Research Council (MRC)
Pathology Society
NHS Specialised Commissioners
NIHR Newcastle Biomedical Research Centre
Wellcome Trust
Wellcome Centre for Mitochondrial Research

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