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

Acta Neuropathologica
Xinyi LiGabriel Pascual

Abstract

Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson's disease (PD). It is hypothesized that α-synuclein pathology spreads by a "prion-like" mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular α-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-α-synuclein antibodies that can potentially be used as markers or immunotherapy, we interrogated peripheral IgG+ memory B cells from PD patients for reactivity to α-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 α-synuclein, aSyn-323.1, aSyn-336.1 and aSyn-338.1, were characterized further and shown to recognize epitopes in the C terminus of α-synuclein with binding affinities between 0.3 and 2.8 μM. Furthermore, all three antibodies were able to neutralize the "seeding" of intracellular synuclein aggregates in an in vitro α-synuclein seeding assay. Finally, differential react...Continue Reading

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Citations

Jan 14, 2020·International Reviews of Immunology·Neema Negi, Bimal K Das
Jul 28, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kirsten M AndersonJill A Hollenbach
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Mar 14, 2021·Journal of Molecular Neuroscience : MN·Mohammadmahdi SabahiNima Rezaei
Jun 30, 2021·NPJ Parkinson's Disease·Anthony R BraunJonathan N Sachs

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Methods Mentioned

BETA
PCR
static light scattering
ELISA
FACS
transfection
flow cytometry
biosensors
biosensor
Isothermal Titration Calorimetry
biolayer

Software Mentioned

IgBlast

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