Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology

Deposition of alpha-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson's disease (PD). It is hypothesized that alpha-synuclein pathology spreads by a prion-like mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular -synuclein conformers and/or posttranslational modifications may serve as biomarkers of disease or potential targets for novel interventions. To explore whether the antibody repertoires of PD patients contain anti--synuclein antibodies that can potentially be used as markers or immunotherapy, we interrogated peripheral IgG(+) memory B cells from PD patients for reactivity to -synuclein. In total, ten somatically mutated antibodies were recovered, suggesting the presence of an ongoing antigen-driven immune response. The three antibodies that had the highest affinity to recombinant full-length -synuclein, aSyn-323.1, aSyn-336.1 and aSyn-338.1, were characterized further and shown to recognize epitopes in the C terminus of -synuclein with binding affinities between 0.3 and 2.8M. Furthermore, all three antibodies were able to neutralize the seeding of intracellular synuclein aggregates in an in vitro -synuclein seeding assay. Finally, differential reactivities were observed for all three human anti--synuclein antibodies across tissue treatment conditions by immunohistochemistry. Our results suggest that the memory B-cell repertoire of PD patients might represent a potential source of biomarkers and therapies.