%0 Journal Article
%A Flores-Fernandez, Jose Miguel
%A Pesch, Verena
%A Sriraman, Aishwarya
%A Chimal-Juarez, Enrique
%A Amidian, Sara
%A Wang, Xiongyao
%A Duckering, Caleb
%A Fang, Andrew
%A Reithofer, Sara
%A Ma, Liang
%A Cortez, Leonardo M.
%A Sim, Valerie L.
%A Tamgüney, Gültekin
%A Wille, Holger
%T Rational design of structure‐based vaccines targeting misfolded alpha‐synuclein conformers of Parkinson's disease and related disorders
%J Bioengineering & translational medicine
%V 9
%N 4
%@ 2380-6761
%C Hoboken, NJ
%I Wiley
%M FZJ-2024-05985
%P e10665
%D 2024
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ 39036077
%U <Go to ISI:>//WOS:001198609000001
%R 10.1002/btm2.10665
%U https://juser.fz-juelich.de/record/1032082