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bioRxiv · 10.1101/2023.10.27.564328

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

Lieknina, I.·Pantelejevs, T.·Lends, A.·Reimer, L.·Jaudzems, K.·El-Turabi, A.·Gram, H.·Jensen, P. H.·Tars, K.
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Abstract

Intraneuronal -synuclein inclusions in the brain are hallmarks of so-called Lewy body diseases - Parkinsons disease and Dementia with Lewy bodies. Lewy bodies are cytoplasmic inclusions, containing mainly aggregated -synuclein together with some other proteins including ubiquitin, neurofilament protein, and alpha B crystallin. In its monomeric form, -synuclein is predominantly localized in nerve terminals, regulating neuronal transmission and synaptic vesicle trafficking. Monomeric -synuclein lacks a well-defined three-dimensional structure and is considered an intrinsically disordered protein. However, in diseased cells -synuclein aggregates into oligomeric and fibrillar amyloid species, which can be detected using aggregate-specific antibodies. Here we investigate the aggregate specificity of rabbit monoclonal MJFR14-6-4-2 antibodies, preferentially recognizing aggregated -synuclein species. We conclude that partial masking of epitope in unstructured monomer in combination with a high local concentration of epitopes instead of distinct epitope conformation is the main reason for apparent selectivity towards various aggregates, including oligomers, fibrils, and artificial virus-like particle constructs bearing multiple copies of the MJFR14-6-4-2 epitope. Based on the structural insight, we were able to express mutant -synuclein that when fibrillated are unable to bind MJFR14-6-4-2. Using these "stealth" fibrils as a tool for seeding cellular -synuclein aggregation, provides superior signal/noise ratio for detection of cellular -synuclein aggregates by MJFR14-6-4-2 immunocytochemistry. Our data provide a molecular level understanding of specific recognition of toxic amyloid oligomers, which is critical for the development of inhibitors against synucleinopathies.

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Lieknina, I., Pantelejevs, T., Lends, A., Reimer, L., Jaudzems, K., El-Turabi, A., Gram, H., Jensen, P. H., Tars, K.. 2023-11-01. Structural basis of epitope recognition by anti-alpha synuclein antibodies MJFR14-6-4-2. https://doi.org/10.1101/2023.10.27.564328

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