Flores-Fernandez Jose Miguel, Pesch Verena, Sriraman Aishwarya, Chimal-Juarez Enrique, Amidian Sara, Wang Xiongyao, Duckering Caleb, Fang Andrew, Reithofer Sara, Ma Liang, Cortez Leonardo M, Sim Valerie L, Tamgüney Gültekin, Wille Holger
Centre for Prions and Protein Folding Diseases University of Alberta Edmonton Alberta Canada.
Department of Biochemistry University of Alberta Edmonton Alberta Canada.
Bioeng Transl Med. 2024 Apr 9;9(4):e10665. doi: 10.1002/btm2.10665. eCollection 2024 Jul.
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.
α-突触核蛋白病，包括帕金森病（PD）、多系统萎缩（MSA）和路易体痴呆（DLB），是由错误折叠的α-突触核蛋白积累引起的神经退行性疾病。开发针对α-突触核蛋白病的有效疫苗具有挑战性，因为难以在不引起有害自身免疫反应的情况下刺激针对α-突触核蛋白的免疫特异性反应，同时仅选择性地靶向α-突触核蛋白的病理形式。以往使用线性肽和表位且未控制抗原结构的尝试在临床试验中失败了。免疫系统无法区分天然α-突触核蛋白及其淀粉样蛋白形式。选择真菌HET-s蛋白的朊病毒结构域作为支架，以引入来自α-突触核蛋白原纤维表面的特定表位。通过在支架蛋白表面引入特定的氨基酸取代，产生了四种候选疫苗。该方法成功模拟了在α-突触核蛋白原纤维中看到的平行对齐β-折叠结构的堆积。所有候选疫苗均诱导产生了大量识别源自α-突触核蛋白病小鼠模型的病理性α-突触核蛋白原纤维的IgG抗体。此外，抗血清识别死于DLB、MSA或PD患者脑裂解物中的病理性α-突触核蛋白聚集体，但不识别线性α-突触核蛋白肽。我们基于利用α-突触核蛋白淀粉样原纤维结构进行疫苗的合理设计、严格控制用于免疫的暴露抗原结构以及模拟聚集的α-突触核蛋白的能力的方法，为开发针对α-突触核蛋白原纤维的有效疫苗提供了一条有前景的途径。
