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抗α-突触核蛋白抗体MJFR14-6-4-2识别表位的结构基础

Structural basis of epitope recognition by anti-alpha-synuclein antibodies MJFR14-6-4-2.

作者信息

Liekniņa Ilva, Reimer Lasse, Panteļejevs Teodors, Lends Alons, Jaudzems Kristaps, El-Turabi Aadil, Gram Hjalte, Hammi Anissa, Jensen Poul Henning, Tārs Kaspars

机构信息

Latvian Biomedical Research and Study Centre, Ratsupites 1, k-1, LV-1067, Riga, Latvia.

University of Aarhus, Danish Research Institute of Translational Neuroscience DANDRITE and Department of Biomedicine, Aarhus, Denmark.

出版信息

NPJ Parkinsons Dis. 2024 Oct 27;10(1):206. doi: 10.1038/s41531-024-00822-y.

DOI:10.1038/s41531-024-00822-y
PMID:39463404
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11514253/
Abstract

Alpha-synuclein (α-syn) inclusions in the brain are hallmarks of so-called Lewy body diseases. Lewy bodies contain mainly aggregated α-syn together with some other proteins. Monomeric α-syn lacks a well-defined three-dimensional structure, but it can aggregate into oligomeric and fibrillar amyloid species, which can be detected using specific antibodies. Here we investigate the aggregate specificity of monoclonal MJFR14-6-4-2 antibodies. We conclude that partial masking of epitope in unstructured monomer in combination with a high local concentration of epitopes is the main reason for MJFR14-6-4-2 selectivity towards aggregates. Based on the structural insight, we produced mutant α-syn that when fibrillated is unable to bind MJFR14-6-4-2. Using these fibrils as a tool for seeding cellular α-syn aggregation, provides superior signal/noise ratio for detection of cellular α-syn aggregates by MJFR14-6-4-2. Our data provide a molecular level understanding of specific recognition of toxic amyloid oligomers, which is critical for the development of inhibitors against synucleinopathies.

摘要

大脑中的α-突触核蛋白（α-syn）包涵体是所谓路易体疾病的标志。路易体主要包含聚集的α-syn以及一些其他蛋白质。单体α-syn缺乏明确的三维结构，但它可以聚集成寡聚体和纤维状淀粉样物质，这些物质可以使用特异性抗体进行检测。在这里，我们研究了单克隆MJFR14-6-4-2抗体的聚集特异性。我们得出结论，无结构单体中表位的部分掩盖与表位的高局部浓度相结合是MJFR14-6-4-2对聚集体具有选择性的主要原因。基于结构上的见解，我们制备了突变型α-syn，其纤维化后无法结合MJFR14-6-4-2。使用这些纤维作为引发细胞α-syn聚集的工具，为MJFR14-6-4-2检测细胞α-syn聚集体提供了更高的信噪比。我们的数据提供了对有毒淀粉样寡聚体特异性识别的分子水平理解，这对于开发针对突触核蛋白病的抑制剂至关重要。

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