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@ARTICLE{FloresFernandez:1032082,
      author       = {Flores-Fernandez, Jose Miguel and Pesch, Verena and
                      Sriraman, Aishwarya and Chimal-Juarez, Enrique and Amidian,
                      Sara and Wang, Xiongyao and Duckering, Caleb and Fang,
                      Andrew and Reithofer, Sara and Ma, Liang and Cortez,
                      Leonardo M. and Sim, Valerie L. and Tamgüney, Gültekin and
                      Wille, Holger},
      title        = {{R}ational design of structure‐based vaccines targeting
                      misfolded alpha‐synuclein conformers of {P}arkinson's
                      disease and related disorders},
      journal      = {Bioengineering $\&$ translational medicine},
      volume       = {9},
      number       = {4},
      issn         = {2380-6761},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {FZJ-2024-05985},
      pages        = {e10665},
      year         = {2024},
      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.},
      cin          = {IBI-7},
      ddc          = {600},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {39036077},
      UT           = {WOS:001198609000001},
      doi          = {10.1002/btm2.10665},
      url          = {https://juser.fz-juelich.de/record/1032082},
}