Journal Article

FZJ-2024-05985

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Rational design of structure‐based vaccines targeting misfolded alpha‐synuclein conformers of Parkinson's disease and related disorders

Flores-Fernandez, J. M. ; Pesch, V. ; Sriraman, A. ; Chimal-Juarez, E. ; Amidian, S. ; Wang, X. ; Duckering, C. ; Fang, A. ; Reithofer, S.FZJ* ; Ma, L.FZJ* ; Cortez, L. M. ; Sim, V. L. ; Tamgüney, G. (Corresponding author)FZJ* ; Wille, H.

2024
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/btm2.10665  doi:10.34734/FZJ-2024-05985

Abstract: Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are neurodegenerative disorders caused by the accumulation of misfolded alpha-synuclein protein. Developing effective vaccines against synucleinopathies is challenging due to the difficulty of stimulating an immune-specific response against alpha-synuclein without causing harmful autoimmune reactions, selectively targeting only pathological forms of alpha-synuclein. Previous attempts using linear peptides and epitopes without control of the antigen structure failed in clinical trials. The immune system was unable to distinguish between native alpha-synuclein and its amyloid form. The prion domain of the fungal HET-s protein was selected as a scaffold to introduce select epitopes from the surface of alpha-synuclein fibrils. Four vaccine candidates were generated by introducing specific amino acid substitutions onto the surface of the scaffold protein. The approach successfully mimicked the stacking of the parallel in-register beta-sheet structure seen in alpha-synuclein fibrils. All vaccine candidates induced substantial levels of IgG antibodies that recognized pathological alpha-synuclein fibrils derived from a synucleinopathy mouse model. Furthermore, the antisera recognized pathological alpha-synuclein aggregates in brain lysates from patients who died from DLB, MSA, or PD, but did not recognize linear alpha-synuclein peptides. Our approach, based on the rational design of vaccines using the structure of alpha-synuclein amyloid fibrils and strict control over the exposed antigen structure used for immunization, as well as the ability to mimic aggregated alpha-synuclein, provides a promising avenue toward developing effective vaccines against alpha-synuclein fibrils.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)

Appears in the scientific report 2024

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