Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Neurology, National Key Clinical, Department and Key Discipline of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
J Neurochem. 2018 Apr;145(1):34-50. doi: 10.1111/jnc.14312. Epub 2018 Mar 25.
Recent studies have strongly shown that cell-to-cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α-synuclein remains unclear. Here, we constructed a cell-to-cell transmission model of α-synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl and α-synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or over-expression. Our results demonstrated that iron promoted α-synuclein aggregation and transmission by inhibiting autophagosome-lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB (TFEB), a master transcriptional regulator of autophagosome-lysosome fusion, and inhibited its nuclear translocation through activating AKT/mTORC1 signaling. After silencing TFEB, ratios of α-synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was over-expressed, the transmission of α-synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α-synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and α-synuclein, and identify TFEB as not only a potential target for preventing α-synuclein transmission, but also a critical factor for iron-induced α-synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α-synuclein transmission in Parkinson's disease.
最近的研究强烈表明，神经致病性蛋白的细胞间传递是神经退行性疾病发展的常见机制。然而，其根本原因很复杂，目前知之甚少。虽然各种疾病的发病机制涉及不同的过程，但它们都具有铁积累的共同特征，这在突触核蛋白病中尤为突出。然而，铁是否是促进α-突触核蛋白传播的辅助因子尚不清楚。在这里，我们使用基于腺病毒载体的 SN4741 细胞系构建了α-突触核蛋白的细胞间传递模型。用 FeCl 处理细胞，然后评估α-突触核蛋白聚集和传递。此外，通过基因敲低或过表达来研究可能的机制。我们的结果表明，铁通过抑制自噬体-溶酶体融合来促进α-突触核蛋白的聚集和传递。此外，铁通过激活 AKT/mTORC1 信号通路降低核转录因子 EB（TFEB）的表达，TFEB 是自噬体-溶酶体融合的主要转录调节因子，并抑制其核转位。沉默 TFEB 后，铁的存在并没有显著改变α-突触核蛋白聚集和传递的比例；另一方面，当 TFEB 过表达时，铁诱导的α-突触核蛋白的传递明显逆转；表明铁促进α-突触核蛋白传递的机制可能是通过 TFEB 介导的。总之，我们的数据揭示了铁和α-突触核蛋白之间以前未知的关系，并确定 TFEB 不仅是预防α-突触核蛋白传递的潜在靶点，也是铁诱导α-突触核蛋白聚集和传递的关键因素。事实上，铁和 TFEB 在突触核蛋白病中的这种新发现的作用可能为开发预防帕金森病中α-突触核蛋白传递的治疗策略提供新的靶点。
