Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University, Shanghai, China.
Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University, Shanghai, China.
Neurobiol Aging. 2018 Jul;67:67-74. doi: 10.1016/j.neurobiolaging.2018.03.010. Epub 2018 Mar 13.
Parkinson's disease (PD) is a common neurodegenerative disease associated with the progressive loss of dopaminergic neurons in the substantia nigra. Proteinaceous depositions of alpha-synuclein (α-syn) and its mutations, A30P and A53T, are one important characteristic of PD. However, little is known about their aggregation and degradation mechanisms. Dendritic cell factor 1 (DCF1) is a membrane protein that plays important roles in nerve development in mouse. In this study, we aimed to show that DCF1 overexpression in a PD Drosophila model significantly ameliorates impaired locomotor behavior in third instar larvae and normalizes neuromuscular junction growth. Furthermore, climbing ability also significantly increased in adult PD Drosophila. More importantly, the lifespan dramatically extended by an average of approximately 23%, and surprisingly, DCF1 could prevent α-syn-induced dopaminergic neuron loss by aggregating α-syn in the dorsomedial region of Drosophila. Mechanistically, we confirmed that DCF1 could degrade α-syn both in vivo and in vitro. Our findings revealed an important role of DCF1 in PD process and may provide new potential strategies for developing drugs to treat neurodegenerative diseases.
帕金森病（PD）是一种常见的神经退行性疾病，与黑质中多巴胺能神经元的进行性丧失有关。α-突触核蛋白（α-syn）及其突变 A30P 和 A53T 的蛋白沉积是 PD 的一个重要特征。然而，它们的聚集和降解机制知之甚少。树突细胞因子 1（DCF1）是一种在小鼠神经发育中发挥重要作用的膜蛋白。在这项研究中，我们旨在表明在 PD 果蝇模型中过表达 DCF1 可显著改善第三龄幼虫运动行为受损，并使神经肌肉接头生长正常化。此外，成年 PD 果蝇的攀爬能力也显著提高。更重要的是，寿命平均延长了约 23%，令人惊讶的是，DCF1 可以通过将 α-syn 聚集在果蝇的背内侧区域来防止 α-syn 诱导的多巴胺能神经元丧失。从机制上讲，我们证实 DCF1 可以在体内和体外降解 α-syn。我们的研究结果揭示了 DCF1 在 PD 发病机制中的重要作用，并可能为开发治疗神经退行性疾病的药物提供新的潜在策略。
