Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, Philadelphia, PA, 19140, USA.
Cell Death Dis. 2020 Oct 8;11(10):835. doi: 10.1038/s41419-020-03033-4.
HIV-1 Tat is a potent neurotoxic protein that is released by HIV-1 infected cells in the brain and perturbs neuronal homeostasis, causing a broad range of neurological disorders in people living with HIV-1. Furthermore, the effects of Tat have been addressed in numerous studies to investigate the molecular events associated with neuronal cells survival and death. Here, we discovered that exposure of rat primary neurons to Tat resulted in the up-regulation of an uncharacterized long non-coding RNA (lncRNA), LOC102549805 (lncRNA-U1). Our observations showed that increased expression of lncRNA-U1 in neurons disrupts bioenergetic pathways by dysregulating homeostasis of Ca, mitigating mitochondrial oxygen reduction, and decreasing ATP production, all of which point mitochondrial impairment in neurons via the Tat-mediated lncRNA-U1 induction. These changes were associated with imbalances in autophagy and apoptosis pathways. Additionally, this study showed the ability of Tat to modulate expression of the neuropeptide B/W receptor 1 (NPBWR1) gene via up-regulation of lncRNA-U1. Collectively, our results identified Tat-mediated lncRNA-U1 upregulation resulting in disruption of neuronal homeostasis.
HIV-1 Tat 是一种有效的神经毒性蛋白，由感染 HIV-1 的脑细胞释放，破坏神经元内环境稳定，导致 HIV-1 感染者出现广泛的神经紊乱。此外，已有大量研究针对 Tat 的作用展开研究，以探究与神经元细胞存活和死亡相关的分子事件。在这里，我们发现 Tat 暴露会导致大鼠原代神经元中一个未被阐明的长链非编码 RNA（lncRNA），LOC102549805（lncRNA-U1）的上调。我们的观察表明，神经元中 lncRNA-U1 的表达增加会通过扰乱 Ca 的内环境平衡、减轻线粒体氧还原和减少 ATP 产生来破坏能量代谢途径，所有这些都表明 Tat 通过诱导 lncRNA-U1 导致神经元中线粒体损伤。这些变化与自噬和细胞凋亡途径的失衡有关。此外，这项研究还表明 Tat 能够通过上调 lncRNA-U1 来调节神经肽 B/W 受体 1（NPBWR1）基因的表达。总的来说，我们的结果表明 Tat 介导的 lncRNA-U1 上调导致神经元内环境稳定的破坏。
