MJF-14 proximity ligation assay detects early non-inclusion alpha-synuclein pathology with enhanced specificity and sensitivity

Jensen, Nanna Møller, Fu, YuHong, Betzer, Cristine, Li, Hongyun, Elfarrash, Sara, Shaib, Ali H., Krah, Donatus, Vitic, Zagorka, Reimer, Lasse, Gram, Hjalte, Buchman, Vladimir ORCID: https://orcid.org/0000-0002-7631-8352, Denham, Mark, Rizzoli, Silvio O., Halliday, Glenda M. and Jensen, Poul Henning 2024. MJF-14 proximity ligation assay detects early non-inclusion alpha-synuclein pathology with enhanced specificity and sensitivity. npj Parkinson's Disease 10 , 227. 10.1038/s41531-024-00841-9

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Abstract

α-Synuclein proximity ligation assay (PLA) has proved a sensitive technique for detection of non-Lewy body α-synuclein aggregate pathology. Here, we describe the MJF-14 PLA, a new PLA towards aggregated α-synuclein with unprecedented specificity, using the aggregate-selective α-synuclein antibody MJFR-14-6-4-2 (hereafter MJF-14). Signal in the assay correlates with α-synuclein aggregation in cell culture and human neurons, induced by α-synuclein overexpression or pre-formed fibrils. Co-labelling of MJF-14 PLA and pS129-α-synuclein immunofluorescence in post-mortem cases of dementia with Lewy bodies shows that while the MJF-14 PLA reveals extensive non-inclusion pathology, it is not sensitive towards pS129-α-synuclein-positive Lewy bodies. In Parkinson’s disease brain, direct comparison of PLA and immunohistochemistry with the MJF-14 antibody shows widespread α-synuclein pathology preceding the formation of conventional Lewy pathology. In conclusion, we introduce an improved α-synuclein aggregate PLA to uncover abundant non-inclusion pathology, which deserves future validation with brain bank resources and in different synucleinopathies.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	3 December 2024
Date of Acceptance:	17 November 2024
Last Modified:	03 Dec 2024 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/174455

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