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Updated: Jul 1, 2025
Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo
Published on: June 2, 2019
Vaccination with structurally adapted fungal protein fibrils induces immunity to Parkinson's disease
Verena Pesch1, José Miguel Flores-Fernandez2, Sara Reithofer1
1Institut für Biologische Informationsprozesse, Strukturbiochemie (IBI-7), Forschungszentrum Jülich, 52425 Jülich, Germany.
Abstract:
The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, a progressive age-related neurodegenerative disease for which there is no cure. HET-s is a soluble fungal protein that can form assembled amyloid fibrils in its prion state. We engineered HET-s(218-298) to form four different fibrillar vaccine candidates, each displaying a specific conformational epitope present on the surface of α-synuclein fibrils. Vaccination with these four vaccine candidates prolonged the survival of immunized TgM83+/- mice challenged with α-synuclein fibrils by 8% when injected into the brain to model brain-first Parkinson's disease or by 21% and 22% when injected into the peritoneum or gut wall, respectively, to model body-first Parkinson's disease. Antibodies from fully immunized mice recognized α-synuclein fibrils and brain homogenates from patients with Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Conformation-specific vaccines that mimic epitopes present only on the surface of pathological fibrils but not on soluble monomers, hold great promise for protection against Parkinson's disease, related synucleinopathies and other amyloidogenic protein misfolding disorders.
Insights
Novel vaccines targeting misfolded alpha-synuclein fibrils show promise for Parkinson's disease. Immunization extended survival in mouse models, offering hope for synucleinopathies and other amyloid disorders.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Parkinson's disease is a neurodegenerative disorder caused by pathological alpha-synuclein misfolding and aggregation.
- Currently, no cure exists for Parkinson's disease, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To develop conformation-specific vaccines targeting alpha-synuclein fibrils.
- To evaluate the efficacy of these vaccines in preventing or treating Parkinson's disease models.
Main Methods:
- Engineered the fungal protein HET-s(218-298) into four fibrillar vaccine candidates displaying specific epitopes.
- Vaccinated TgM83+/- mice and challenged them with alpha-synuclein fibrils to model Parkinson's disease.
- Assessed survival rates and antibody recognition of alpha-synuclein fibrils and patient brain homogenates.
Main Results:
- Vaccination prolonged survival in mice challenged with alpha-synuclein fibrils, with significant increases observed in body-first models (21-22%) and brain-first models (8%).
- Antibodies generated recognized pathological alpha-synuclein fibrils and brain tissues from Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy patients.
Conclusions:
- Conformation-specific vaccines targeting pathological alpha-synuclein fibrils offer a promising therapeutic approach.
- These vaccines hold potential for protecting against Parkinson's disease, related synucleinopathies, and other amyloidogenic protein misfolding disorders.
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