Involvement of C/EBPβ-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis. (15th September 2019)

• Record Type: Journal Article
• Authors: Huang, Enping; Huang, Hongyan; Guan, Tianshan; Liu, Chao; Qu, Dong; Xu, Yue; Yang, Jiao; Yan, Lei; Xiong, Yahui; Liang, Ting; Wang, Qi; Chen, Ling
• Is Part Of: Toxicology letters. Volume 312(2019)
• Page Start: 11
• Page End: 21
• Publication Date: 2019-09-15
• Subjects: C/EBP CCAAT-enhancer binding proteins -- METH methamphetamine -- DDIT4 DNA damage-inducible transcript 4 -- mTOR mammalian target of rapamycin -- Trib3 tribbles homolog 3 -- α-syn alpha-synuclein -- TSC2 tuberous sclerosis complex 2 -- PD Parkinson's disease -- SH-SY5Y cell a human neuroblastoma cell line -- SD Rats Sprague-Dawley (SD) rats -- GFP Green fluorescent protein; Methamphetamine (METH) -- C/EBPβ -- Neurotoxicity -- Apoptosis -- Autophagy; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.05.003
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: C/EBPβ is involved in METH-induced autophagy and apoptosis through DDIT4/TSC2/mTOR signal axis and Trib3/Parkin/α-syn signaling pathway. Highlights: Methamphetamine (METH) exposure increased p-TSC2/TSC2 protein expression ratio, decreased Parkin protein level. C/EBPβ is involved in METH-induced autophagy through DDIT4/TSC2/mTOR signaling pathway. C/EBPβ is involved in METH-induced apoptosis through Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Abstract: Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein β (C/EBPβ) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPβ is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPβ, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPβ on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPβ lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPβ, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPβ, DDIT4, Trib3 or α-syn, or by Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPβ protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPβ plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.