Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
Institute for Research and Continuing Education, Hong Kong Baptist University, 518000 Shenzhen, China.
Int J Mol Sci. 2020 Feb 22;21(4):1515. doi: 10.3390/ijms21041515.
bstract TFEB (transcription factor EB), which is a master regulator of autophagy and lysosome biogenesis, is considered to be a new therapeutic target for Parkinson's disease (PD). However, only several small-molecule TFEB activators have been discovered and their neuroprotective effects in PD are unclear. In this study, a curcumin derivative, named E4, was identified as a potent TFEB activator. Compound E4 promoted the translocation of TFEB from cytoplasm into nucleus, accompanied by enhanced autophagy and lysosomal biogenesis. Moreover, TFEB knockdown effectively attenuated E4-induced autophagy and lysosomal biogenesis. Mechanistically, E4-induced TFEB activation is mainly through AKT-MTORC1 inhibition. In the PD cell models, E4 promoted the degradation of α-synuclein and protected against the cytotoxicity of MPP (1-methyl-4-phenylpyridinium ion) in neuronal cells. Overall, the TFEB activator E4 deserves further study in animal models of neurodegenerative diseases, including PD.
摘要 TFEB（转录因子 EB）是自噬和溶酶体生物发生的主要调节因子，被认为是帕金森病（PD）的新治疗靶点。然而，目前仅发现了几种小分子 TFEB 激活剂，其在 PD 中的神经保护作用尚不清楚。在本研究中，发现了一种姜黄素衍生物，命名为 E4，它是一种有效的 TFEB 激活剂。化合物 E4 促进 TFEB 从细胞质向核内易位，同时增强自噬和溶酶体生物发生。此外，TFEB 敲低有效减弱了 E4 诱导的自噬和溶酶体生物发生。机制上，E4 诱导的 TFEB 激活主要通过 AKT-MTORC1 抑制实现。在 PD 细胞模型中，E4 促进了 α-突触核蛋白的降解，并保护神经元细胞免受 MPP+（1-甲基-4-苯基吡啶离子）的细胞毒性。总之，TFEB 激活剂 E4 值得在包括 PD 在内的神经退行性疾病的动物模型中进一步研究。
