Spencer Brian, Emadi Sharareh, Desplats Paula, Eleuteri Simona, Michael Sarah, Kosberg Kori, Shen Jay, Rockenstein Edward, Patrick Christina, Adame Anthony, Gonzalez Tania, Sierks Michael, Masliah Eliezer
NeuroTransit, Inc., San Diego, California, USA.
Department of Chemical Engineering, Arizona State University, Tempe, Arizona, USA.
Mol Ther. 2014 Oct;22(10):1753-1767. doi: 10.1038/mt.2014.129. Epub 2014 Jul 10.
Parkinson's disease and dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of α-synuclein (α-syn). Recently, single-chain fragment variables (scFVs) have been developed against individual conformational species of α-syn. Unlike more traditional monoclonal antibodies, these scFVs will not activate or be endocytosed by Fc receptors. For this study, we investigated an scFV directed against oligomeric α-syn fused to the LDL receptor-binding domain from apolipoprotein B (apoB). The modified scFV showed enhanced brain penetration and was imported into neuronal cells through the endosomal sorting complex required for transport (ESCRT) pathway, leading to lysosomal degradation of α-syn aggregates. Further analysis showed that the scFV was effective at ameliorating neurodegenerative pathology and behavioral deficits observed in the mouse model of dementia with Lewy bodies/Parkinson's disease. Thus, the apoB modification had the effect of both increasing accumulation of the scFV in the brain and directing scFV/α-syn complexes for degradation through the ESCRT pathway, leading to improved therapeutic potential of immunotherapy.
帕金森病和路易体痴呆是由α-突触核蛋白（α-syn）聚集所特征的神经退行性疾病。最近，已开发出针对α-syn个别构象形式的单链抗体片段（scFVs）。与更传统的单克隆抗体不同，这些scFVs不会被Fc受体激活或内吞。在本研究中，我们研究了一种针对与载脂蛋白B（apoB）的低密度脂蛋白受体结合域融合的寡聚α-syn的scFV。修饰后的scFV显示出增强的脑渗透能力，并通过运输所需的内体分选复合物（ESCRT）途径导入神经元细胞，导致α-syn聚集体的溶酶体降解。进一步分析表明，该scFV在改善路易体痴呆/帕金森病小鼠模型中观察到的神经退行性病理和行为缺陷方面是有效的。因此，apoB修饰具有增加scFV在脑中积累以及引导scFV/α-syn复合物通过ESCRT途径进行降解的作用，从而提高了免疫治疗的治疗潜力。
