针对帕金森病及相关疾病中折叠错误的α-突触核蛋白构象,合理设计基于结构的疫苗

IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Bioengineering & Translational Medicine Pub Date : 2024-04-09 DOI:10.1002/btm2.10665
Jose Miguel Flores-Fernandez, Verena Pesch, Aishwarya Sriraman, Enrique Chimal-Juarez, Sara Amidian, Xiongyao Wang, Caleb Duckering, Andrew Fang, Sara Reithofer, Liang Ma, Leonardo M. Cortez, Valerie L. Sim, Gültekin Tamgüney, Holger Wille
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引用次数: 0

摘要

包括帕金森病 (PD)、多系统萎缩症 (MSA) 和路易体痴呆症 (DLB) 在内的突触核蛋白病是一种由错误折叠的α-突触核蛋白堆积引起的神经退行性疾病。开发针对突触核蛋白病的有效疫苗具有挑战性,因为很难激发针对α-突触核蛋白的免疫特异性反应而不引起有害的自身免疫反应,只能选择性地针对病理形式的α-突触核蛋白。以前使用线性肽和表位而不控制抗原结构的尝试在临床试验中失败了。免疫系统无法区分原生α-突触核蛋白及其淀粉样形式。我们选择真菌 HET-s 蛋白的朊病毒结构域作为支架,从α-突触核蛋白纤维表面引入精选表位。通过在支架蛋白表面引入特定氨基酸取代,产生了四种候选疫苗。这种方法成功地模拟了阿尔法-突触核蛋白纤维中的平行排列β片状结构。所有候选疫苗都能诱导大量 IgG 抗体,这些抗体能识别来自突触核蛋白病小鼠模型的病理α-突触核蛋白纤维。此外,抗血清还能识别死于DLB、MSA或PD的患者脑裂解物中的病理性α-突触核蛋白聚集体,但不能识别线性α-突触核蛋白肽。我们的方法基于利用α-突触核蛋白淀粉样纤维结构合理设计疫苗、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,为开发针对α-突触核蛋白纤维的有效疫苗提供了一条前景广阔的途径。
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Rational design of structure-based vaccines targeting misfolded alpha-synuclein conformers of Parkinson's disease and related disorders

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.

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来源期刊
Bioengineering & Translational Medicine
Bioengineering & Translational Medicine Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
8.40
自引率
4.10%
发文量
150
审稿时长
12 weeks
期刊介绍: Bioengineering & Translational Medicine, an official, peer-reviewed online open-access journal of the American Institute of Chemical Engineers (AIChE) and the Society for Biological Engineering (SBE), focuses on how chemical and biological engineering approaches drive innovative technologies and solutions that impact clinical practice and commercial healthcare products.
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