Abstract

The translocation of transcription factor EB (TFEB) to the nucleus plays a pivotal role in the regulation of basic cellular processes, such as lysosome biogenesis and autophagy. Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, which is important in maintaining cellular homeostasis during environmental stress. Furthermore, oxidative stress is a critical cause for the progression of neurodegenerative diseases. Curcumin has anti-oxidative and anti-inflammatory activities, and is expected to have potential therapeutic effects in various diseases. In this study, we demonstrated that curcumin regulated TFEB export signalling via inhibition of glycogen synthase kinase-3β (GSK-3β); GSK-3β was inactivated by curcumin, leading to reduced phosphorylation of TFEB. We further showed that H₂O₂-induced oxidative stress was reduced by curcumin via the Nrf2/HO-1 pathway in human neuroblastoma cells. In addition, we showed that curcumin induced the degradation of amyloidogenic proteins, including amyloid-β precursor protein and α-synuclein, through the TFEB-autophagy/lysosomal pathway. In conclusion, curcumin regulates autophagy by controlling TFEB through the inhibition of GSK-3β, and increases antioxidant gene expression in human neuroblastoma cells. These results contribute to the development of novel cellular therapies for neurodegenerative diseases.

摘要

转录因子 EB (TFEB) 向细胞核的易位在基本细胞过程的调节中起关键作用，例如溶酶体生物发生和自噬。自噬是一种细胞内降解系统，可将细胞质成分输送到溶酶体，这对于在环境压力下维持细胞稳态很重要。此外，氧化应激是神经退行性疾病进展的关键原因。姜黄素具有抗氧化和抗炎活性，有望对多种疾病具有潜在的治疗作用。在这项研究中，我们证明姜黄素通过以下方式调节 TFEB 输出信号抑制糖原合酶激酶-3β (GSK-3β)；GSK-3β 被姜黄素灭活，导致 TFEB 磷酸化降低。我们进一步表明，姜黄素通过人神经母细胞瘤细胞中的 Nrf2/HO-1 通路降低了H ₂ O ₂诱导的氧化应激。此外，我们发现姜黄素通过 TFEB-自噬/溶酶体途径诱导淀粉样蛋白的降解，包括淀粉样蛋白 β 前体蛋白和 α-突触核蛋白。总之，姜黄素通过抑制 GSK-3β 控制 TFEB 来调节自噬，并增加人神经母细胞瘤细胞中抗氧化基因的表达。这些结果有助于开发用于神经退行性疾病的新型细胞疗法。