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001032082 1001_ $$0P:(DE-HGF)0$$aFlores-Fernandez, Jose Miguel$$b0
001032082 245__ $$aRational design of structure‐based vaccines targeting misfolded alpha‐synuclein conformers of Parkinson's disease and related disorders
001032082 260__ $$aHoboken, NJ$$bWiley$$c2024
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001032082 520__ $$aSynucleinopathies, 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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001032082 7001_ $$0P:(DE-Juel1)178945$$aPesch, Verena$$b1
001032082 7001_ $$0P:(DE-HGF)0$$aSriraman, Aishwarya$$b2
001032082 7001_ $$0P:(DE-HGF)0$$aChimal-Juarez, Enrique$$b3
001032082 7001_ $$0P:(DE-HGF)0$$aAmidian, Sara$$b4
001032082 7001_ $$0P:(DE-HGF)0$$aWang, Xiongyao$$b5
001032082 7001_ $$0P:(DE-HGF)0$$aDuckering, Caleb$$b6
001032082 7001_ $$0P:(DE-HGF)0$$aFang, Andrew$$b7
001032082 7001_ $$0P:(DE-Juel1)185633$$aReithofer, Sara$$b8
001032082 7001_ $$0P:(DE-Juel1)180536$$aMa, Liang$$b9
001032082 7001_ $$0P:(DE-HGF)0$$aCortez, Leonardo M.$$b10
001032082 7001_ $$0P:(DE-HGF)0$$aSim, Valerie L.$$b11
001032082 7001_ $$0P:(DE-Juel1)177986$$aTamgüney, Gültekin$$b12$$eCorresponding author
001032082 7001_ $$0P:(DE-HGF)0$$aWille, Holger$$b13
001032082 773__ $$0PERI:(DE-600)2865162-5$$a10.1002/btm2.10665$$gVol. 9, no. 4, p. e10665$$n4$$pe10665$$tBioengineering & translational medicine$$v9$$x2380-6761$$y2024
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