TY  - JOUR
AU  - Flores-Fernandez, Jose Miguel
AU  - Pesch, Verena
AU  - Sriraman, Aishwarya
AU  - Chimal-Juarez, Enrique
AU  - Amidian, Sara
AU  - Wang, Xiongyao
AU  - Duckering, Caleb
AU  - Fang, Andrew
AU  - Reithofer, Sara
AU  - Ma, Liang
AU  - Cortez, Leonardo M.
AU  - Sim, Valerie L.
AU  - Tamgüney, Gültekin
AU  - Wille, Holger
TI  - Rational design of structure‐based vaccines targeting misfolded alpha‐synuclein conformers of Parkinson's disease and related disorders
JO  - Bioengineering & translational medicine
VL  - 9
IS  - 4
SN  - 2380-6761
CY  - Hoboken, NJ
PB  - Wiley
M1  - FZJ-2024-05985
SP  - e10665
PY  - 2024
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 39036077
UR  - <Go to ISI:>//WOS:001198609000001
DO  - DOI:10.1002/btm2.10665
UR  - https://juser.fz-juelich.de/record/1032082
ER  -