针对细胞毒性α-突触核蛋白寡聚体的单克隆抗体的分子特性和诊断潜力

IF 6.7 1区 医学 Q1 NEUROSCIENCES
Janni Nielsen, Johanne Lauritsen, Jannik N. Pedersen, Jan S. Nowak, Malthe K. Bendtsen, Giulia Kleijwegt, Kaija Lusser, Laia C. Pitarch, Julián V. Moreno, Matthias M. Schneider, Georg Krainer, Louise Goksøyr, Paul Khalifé, Sanne Simone Kaalund, Susana Aznar, Magnus Kjærgaard, Vita Sereikaité, Kristian Strømgaard, Tuomas P. J. Knowles, Morten Agertoug Nielsen, Adam F. Sander, Marina Romero-Ramos, Daniel E. Otzen
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引用次数: 0

摘要

α-突触核蛋白(α-syn)以不溶性淀粉样蛋白的形式积聚,但也会形成可溶性α-syn寡聚体(αSOs),这种寡聚体被认为比纤维更具有细胞毒性。为了检测和阻断这些α-SOs的不良活性,我们针对不同形式的α-SOs培养了30种单克隆抗体(mAbs),其中包括未修饰的α-SOs、由脂质过氧化产物和多酚稳定的α-SOs、由C端截短的α-syn形成的α-SOs,以及α-syn在囊病毒样颗粒(cVLPs)上的多价显示。虽然 mAbs 通常偏好 αSOs,但它们也结合纤维,只是结合程度不同。总体而言,我们观察到 mAbs 对单体和 αSOs 的相对亲和力存在很大差异,对 α-syn C 端延伸的要求各不相同,对 α-syn 纤维化的影响不大。在溶液研究中,几种 mAbs 对 αSOs 的偏好程度比对单体的偏好程度高出几个数量级,而商用抗体 MJF14 与 αSOs 的结合强度仅是α-syn 单体的 10 倍。令人欣慰的是,有七种 mAbs 几乎完全阻断了 αSO 对膜囊泡的渗透作用。所选的五种 mAbs 发现了路易体(LBs)、路易神经元以及胶质细胞质包涵体等与α-syn 相关的病理现象,这些病理现象出现在被诊断为帕金森病、伴有路易体的痴呆症或多系统萎缩症患者的死后大脑中,只是程度不同而已。三种 mAbs 对包括早期帕金森氏症在内的死后脑组织病理评估特别有用。尽管这些 mAbs 的生物物理特性和免疫组化特性之间没有直接的联系,但令人鼓舞的是,这些能在体外识别不同聚集的 α-syn 种类的 mAbs 组合也具有诊断潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Molecular properties and diagnostic potential of monoclonal antibodies targeting cytotoxic α-synuclein oligomers

Molecular properties and diagnostic potential of monoclonal antibodies targeting cytotoxic α-synuclein oligomers

α-Synuclein (α-syn) accumulates as insoluble amyloid but also forms soluble α-syn oligomers (αSOs), thought to be even more cytotoxic than fibrils. To detect and block the unwanted activities of these αSOs, we have raised 30 monoclonal antibodies (mAbs) against different forms of αSOs, ranging from unmodified αSOs to species stabilized by lipid peroxidation products and polyphenols, αSOs formed by C-terminally truncated α-syn, and multivalent display of α-syn on capsid virus-like particles (cVLPs). While the mAbs generally show a preference for αSOs, they also bind fibrils, but to variable extents. Overall, we observe great diversity in the mAbs’ relative affinities for monomers and αSOs, varied requirements for the C-terminal extension of α-syn, and only a modest effect on α-syn fibrillation. Several mAbs show several orders of magnitude preference for αSOs over monomers in in-solution studies, while the commercial antibody MJF14 only bound 10-fold more strongly to αSOs than monomeric α-syn. Gratifyingly, seven mAbs almost completely block αSO permeabilization of membrane vesicles. Five selected mAbs identified α-syn-related pathologies like Lewy bodies (LBs) and Lewy Neurites, as well as Glial Cytoplasmic Inclusions in postmortem brains from people diagnosed for PD, dementia with LBs or multiple system atrophy, although to different extents. Three mAbs were particularly useful for pathological evaluation of postmortem brain human tissue, including early stages of PD. Although there was no straightforward connection between the mAbs’ biophysical and immunohistochemical properties, it is encouraging that this comprehensive collection of mAbs able to recognize different aggregated α-syn species in vitro also holds diagnostic potential.

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来源期刊
NPJ Parkinson's Disease
NPJ Parkinson's Disease Medicine-Neurology (clinical)
CiteScore
9.80
自引率
5.70%
发文量
156
审稿时长
11 weeks
期刊介绍: npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
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