Vaccines mimicking conformational epitopes on α-synuclein fibrils provide immunity to Parkinson's disease.

Abstract

The progressive age-related aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, Lewy body dementia and multiple system atrophy, all of which are neurodegenerative diseases without a cure. Because α-synuclein is a self-antigen, pathogenic α-synuclein aggregates do not elicit a strong immune response. Recent advances in structural biology elucidating the structure of α-synuclein fibrils have allowed us to design engineered protein fibrils that model conformational epitopes present on the surface of α-synuclein fibrils. HET-s is a soluble fungal protein capable of forming amyloid fibrils. We used HET-s(218-298) fibrils and four modified derivatives, each displaying a selected conformational epitope present on the surface of α-synuclein fibrils, to vaccinate TgM83+/- mice, a model for Parkinson's disease-like synucleinopathies. Fibrillar vaccine candidates significantly extended the survival of immunized TgM83+/- mice by ≤38% after intraperitoneal challenge and ≤42% after intragastric challenge with α-synuclein fibrils. Fully immunized mice developed antibodies that recognized α-synuclein fibrils and brain homogenates from patients with dementia with Lewy bodies, multiple system atrophy and Parkinson's disease. Fibrillar vaccine candidates that mimic conformational epitopes on the surface of pathological α-synuclein fibrils have the ability to induce immunity and protection against Parkinson's disease and other synucleinopathies.