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

IF 6.7 1区医学 Q1 NEUROSCIENCES

NPJ Parkinson's Disease Pub Date : 2024-11-29 DOI:10.1038/s41531-024-00841-9

Nanna Møller Jensen, YuHong Fu, Cristine Betzer, Hongyun Li, Sara Elfarrash, Ali H. Shaib, Donatus Krah, Zagorka Vitic, Lasse Reimer, Hjalte Gram, Vladimir Buchman, Mark Denham, Silvio O. Rizzoli, Glenda M. Halliday, Poul Henning Jensen

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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.

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MJF-14接近结扎法检测早期非包涵性α -突触核蛋白病理，具有增强的特异性和敏感性

α-突触核蛋白接近结联试验（PLA）已被证明是检测非路易体α-突触核蛋白聚集病理的灵敏技术。在这里，我们利用α-synuclein抗体MJFR-14-6-4-2（以下简称MJF-14）描述了MJF-14聚乳酸，这是一种针对聚集α-synuclein的新型聚乳酸，具有前所未有的特异性。实验中的信号与细胞培养和人神经元中α-突触核蛋白聚集有关，α-突触核蛋白过表达或预形成原纤维诱导α-突触核蛋白聚集。MJF-14 PLA与pS129-α-突触核蛋白免疫荧光共标记在死后痴呆伴路易体病例中显示，MJF-14 PLA表现出广泛的非包涵病理，但对pS129-α-突触核蛋白阳性的路易体不敏感。在帕金森病大脑中，PLA和免疫组织化学与MJF-14抗体的直接比较显示，在常规Lewy病理形成之前，广泛存在α-突触核蛋白病理。总之，我们引入了改进的α-突触核蛋白聚集体聚乳酸，揭示了丰富的非包涵病理，值得未来用脑库资源和不同的突触核蛋白病理进行验证。

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来源期刊

NPJ Parkinson's Disease Medicine-Neurology (clinical)

CiteScore

9.80

自引率

5.70%

发文量

156

审稿时长

11 weeks

期刊介绍： npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.