Wang Chan, Yang Genmeng, Huang Jian, Tian Yunqing, Leung Chi-Kwan, Miao Lin, Wang Haowei, Li Yi, Huang Yizhen, Teng Hanxin, Liu Liu, Li Juan, Zeng Xiaofeng
NHC Key Laboratory of Drug Addiction Medicine, School of Forensic Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue Chenggong District, Kunming, 650500, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Mol Neurobiol. 2025 May;62(5):6150-6165. doi: 10.1007/s12035-024-04667-7. Epub 2024 Dec 23.
Co-exposure to methamphetamine (METH) abuse and HIV infection exacerbates central nervous system damage. However, the underlying mechanisms of this process remain poorly understood. This study aims to explore the roles of neuronal autophagy in the synergistic damage to the central nervous system caused by METH and HIV proteins. Models of METH and HIV-1 Tat protein (Tat) co-exposure were established using tree shrews, primary neurons, and SH-SY5Y cells. Co-exposure to METH and Tat significantly increased the distance traveled, mean velocity, and stereotyped behaviors of tree shrews in the open field test. Western blot analysis revealed that co-exposure to METH and Tat markedly increased the expression of endoplasmic reticulum stress (ERS)-associated proteins (p-ERK, IRE1, ATF6, and Bip) and autophagy markers (ATG7, ATG5, Beclin1, and LC3II). Conversely, co-exposure to METH and Tat significantly downregulated the expressions of p62 and TRIM13. Immunofluorescence staining demonstrated that pretreatment with the ERS inhibitor 4-PBA or siRNA-TRIM13 rescued the abnormal behaviors induced by METH and Tat co-exposure in tree shrews and restored the expression of ERS-related and autophagy-related proteins. Additionally, TRIM13 was found to interact with autophagy-related proteins, including p62, Beclin1, and LC3II by immunoprecipitation assays. Our findings suggest for the first time that METH and Tat synergistically induce neuronal autophagy through ERS pathways, with TRIM13 playing a pivotal regulatory role in this process.
同时滥用甲基苯丙胺（METH）和感染HIV会加剧中枢神经系统损伤。然而，这一过程的潜在机制仍知之甚少。本研究旨在探讨神经元自噬在METH和HIV蛋白对中枢神经系统协同损伤中的作用。利用树鼩、原代神经元和SH-SY5Y细胞建立了METH和HIV-1 Tat蛋白（Tat）共同暴露模型。在旷场试验中，METH和Tat共同暴露显著增加了树鼩的行进距离、平均速度和刻板行为。蛋白质免疫印迹分析显示，METH和Tat共同暴露显著增加了内质网应激（ERS）相关蛋白（p-ERK、IRE1、ATF6和Bip）和自噬标志物（ATG7、ATG5、Beclin1和LC3II）的表达。相反，METH和Tat共同暴露显著下调了p62和TRIM13的表达。免疫荧光染色表明，用ERS抑制剂4-PBA或siRNA-TRIM13预处理可挽救METH和Tat共同暴露诱导的树鼩异常行为，并恢复ERS相关蛋白和自噬相关蛋白的表达。此外，通过免疫沉淀试验发现TRIM13与包括p62、Beclin1和LC3II在内的自噬相关蛋白相互作用。我们的研究结果首次表明，METH和Tat通过ERS途径协同诱导神经元自噬，TRIM13在此过程中起关键调节作用。
