Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson's disease
Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson's disease
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DOI：
10.1016/j.nbd.2019.104712
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发表时间：
2020-03-01
影响因子：
6.1
通讯作者：
Luk, Kelvin C.
中科院分区：
文献类型：
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作者：
Henderson, Michael X.;Covell, Dustin J.;Luk, Kelvin C.
帕金森病 (PD) 和路易体痴呆 (DLB) 是进行性神经退行性疾病，目前尚无缓解疾病的治疗方法。 PD 和 DLB 的特征是突触蛋白 α-突触核蛋白聚集，并且有令人信服的证据表明这些疾病的进展与致病性 α-突触核蛋白通过患病个体大脑的跨细胞传播有关。因此，针对细胞外致病性 α-突触核蛋白的疗法可能有望减缓或阻止疾病进展。在这方面，有人建议可以施用高度选择性的抗体作为靶向致病蛋白的治疗剂。在当前的研究中，我们使用多重选择标准筛选了一系列抗体，以鉴定那些选择性结合致病性α-突触核蛋白并在α-突触核蛋白病的神经元模型中显示出对病理播种的有效抑制的抗体。在 PD 小鼠模型中测试了一种先导抗体，它能够减少 α-突触核蛋白病理学在大脑中的扩散，并减弱纹状体中多巴胺的减少。这项研究强调了 α-突触核蛋白免疫疗法治疗 PD 和 DLB 的治疗潜力，并提供了筛选 α-突触核蛋白抗体以识别具有首选特性的抗体的框架。
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases for which there is no disease-modifying treatment. PD and DLB are characterized by aggregation of the synaptic protein alpha-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic alpha-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic alpha-synuclein may therefore hold promise for slowing or halting disease progression. In this regard, it has been suggested that highly-selective antibodies can be administered as therapeutic agents targeting pathogenic proteins. In the current study, we screened a series of antibodies using multiple selection criterion to identify those that selectively bind pathogenic alpha-synuclein and show potent inhibition of pathology seeding in a neuronal model of alpha-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of alpha-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of alpha-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of alpha-synuclein antibodies to identify those with preferred properties.