Department of Neurology, Hannover Medical School, Hannover, D-30625, Germany.
Department of Neurology, Technical University of Munich (TUM), D-81675, Munich, Germany.
Mol Neurobiol. 2022 Jul;59(7):3980-3995. doi: 10.1007/s12035-022-02824-4. Epub 2022 Apr 22.
Spreading of alpha-synuclein (αSyn) may play an important role in Parkinson's disease and related synucleinopathies. Passive immunization with anti-αSyn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive which specific characteristics are essential to render therapeutic antibodies efficacious. Here, we established a neuronal co-culture model, in which αSyn species are being released from αSyn-overexpressing cells and induce toxicity in a priori healthy GFP-expressing cells. In this model, we investigated the protective efficacy of three anti-αSyn antibodies. Only two of these antibodies, one C-terminal and one N-terminal, protected from αSyn-induced toxicity by inhibiting the uptake of spreading-competent αSyn from the cell culture medium. Neither the binding epitope nor the affinity of the antibodies towards recombinant αSyn could explain differences in biological efficacy. However, both protective antibodies formed more stable antibody-αSyn complexes than the non-protective antibody. These findings indicate that the stability of antibody-αSyn complexes may be more important to confer protection than the binding epitope or affinity to recombinant αSyn.
α-突触核蛋白（αSyn）的扩散可能在帕金森病和相关的突触核蛋白病中发挥重要作用。用抗αSyn 抗体进行被动免疫是一种很有前途的方法，可以减缓扩散过程，从而减缓突触核蛋白病的进展。目前，尚不清楚使治疗性抗体有效的具体特征是什么。在这里，我们建立了一个神经元共培养模型，在该模型中，αSyn 物种从过表达 αSyn 的细胞中释放出来，并在前瞻性健康的 GFP 表达细胞中诱导毒性。在该模型中，我们研究了三种抗αSyn 抗体的保护效果。只有两种抗体，一种是 C 端的，一种是 N 端的，通过抑制从细胞培养基中摄取有扩散能力的 αSyn，从而防止 αSyn 诱导的毒性。抗体对重组 αSyn 的结合表位和亲和力都不能解释其生物学功效的差异。然而，两种保护性抗体形成的抗体-αSyn 复合物比非保护性抗体更稳定。这些发现表明，与结合表位或对重组 αSyn 的亲和力相比，抗体-αSyn 复合物的稳定性对于提供保护可能更为重要。
