Objective: Determine whether alpha-synuclein derived from Parkinson’s disease (PD) and multiple system atrophy (MSA) brains has different conformations as defined by biochemical and antibody-based approaches.

Background: There is evidence in multiple neurodegenerative diseases for cell-to-cell transmission of misfolded forms of protein with the resultant spread of pathologic protein aggregates throughout the brain. In synucleinopathies such as PD and MSA there is also growing support for the idea that different conformations of alpha-synuclein underlie the clinical and pathologic differences seen in these two diseases. In prior studies we found alpha-synuclein seeding ability present in both PD and MSA brain extracts using a cell-based FRET assay. Here we use biochemical and antibody-based means to further define differences between alpha-synuclein in these two diseases.

Methods: Brain tissue from patients with PD and MSA was serially extracted to yield buffer-soluble and detergent-insoluble fractions. We used both commercially available antibodies and also novel antibodies generated to both recombinant fibrils and monomeric alpha-synuclein to test PD and MSA fractions for binding of alpha-synuclein by immunoprecipitation.  The forms of alpha-synuclein bound to the antibodies were tested for ability to induce aggregation in the cell-based assay.

Results: There were distinct differences in the ability of various antibodies to bind to alpha-synuclein from PD vs MSA.  Several antibodies were able to bind a form of alpha-synuclein which was capable of seeding further synuclein aggregation in the cell-based assay from MSA samples, but not from PD samples. 

Conclusions: Differential antibody binding implies that different epitopes are available for binding in the aggregated state, and these findings support the idea that alpha-synuclein in PD and MSA are different in conformation.  Another possibility is that post-translational modifications such as phosphorylation may interfere with antibody binding however this is less likely given the differential binding was maintained across different antibodies with different epitopes.  The conformational differences seen may underlie the diverse clinical and pathologic characteristics of these two synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/antibody-binding-differences-in-alpha-synuclein-from-parkinsons-disease-and-multiple-system-atrophy/