Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson’s patients

Abstract

Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

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Item Type:	Article
Authors/Creators:	de Boni, L. https://orcid.org/0000-0001-7785-482X Wallis, A. Hays Watson, A. Ruiz-Riquelme, A. https://orcid.org/0000-0001-6581-7132 Leyland, L.-A. Bourinaris, T. Hannaway, N. Wüllner, U. Peters, O. Priller, J. https://orcid.org/0000-0001-7596-0979 Falkenburger, B.H. Wiltfang, J. https://orcid.org/0000-0003-1492-5330 Bähr, M. Zerr, I. Bürger, K. Perneczky, R. https://orcid.org/0000-0003-1981-7435 Teipel, S. Löhle, M. Hermann, W. Schott, B.-H. https://orcid.org/0000-0002-8237-4481 Brockmann, K. Spottke, A. Haustein, K. Breuer, P. Houlden, H. Weil, R.S. https://orcid.org/0000-0002-5092-6325 Bartels, T. https://orcid.org/0000-0002-4071-5612
Copyright, Publisher and Additional Information:	© 2024 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Alpha-synuclein; Blood; Human; Parkinson’s disease; Tetramer; Humans; alpha-Synuclein; Parkinson Disease; Aged; Male; Female; Middle Aged; Protein Multimerization; Protein Aggregates
Dates:	Published: 15 July 2024 Published (online): 5 June 2024 Accepted: 17 May 2024
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	02 Aug 2024 09:41
Last Modified:	02 Aug 2024 09:41
Published Version:	http://dx.doi.org/10.1038/s44321-024-00083-5
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s44321-024-00083-5
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:215606

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Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson’s patients

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