Molecular Studies of Neurodegenerative Diseases Lab; FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine - Temple University Philadelphia, PA 19140, USA.
Molecular Studies of Neurodegenerative Diseases Lab; FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine - Temple University Philadelphia, PA 19140, USA.
Mitochondrion. 2023 May;70:31-40. doi: 10.1016/j.mito.2023.03.003. Epub 2023 Mar 15.
For over two decades, highly active antiretroviral therapy (HAART) was able to help prolong the life expectancy of people living with HIV-1 (PLWH) and eliminate the virus to an undetectable level. However, an increased prevalence of HIV- associated neurocognitive disorders (HAND) was observed. These symptoms range from neuronal dysfunction to cell death. Among the markers of neuronal deregulation, we cite the alteration of synaptic plasticity and neuronal communications. Clinically, these dysfunctions led to neurocognitive disorders such as learning alteration and loss of spatial memory, which promote premature brain aging even in HAART-treated patients. In support of these observations, we showed that the gp120 protein deregulates miR-499-5p and its downstream target, the calcineurin (CaN) protein. The gp120 protein also promotes the accumulation of calcium (Ca) and reactive oxygen species (ROS) inside the neurons leading to the activation of CaN and the inhibition of miR-499-5p. gp120 protein also caused mitochondrial fragmentation and changes in shape and size. The use of mimic miR-499 restored mitochondrial functions, appearance, and size. These results demonstrated the additional effect of the gp120 protein on neurons through the miR-499-5p/calcineurin pathway.
二十多年来，高效抗逆转录病毒疗法 (HAART) 能够帮助延长人类免疫缺陷病毒 1 型 (PLWH) 患者的预期寿命，并将病毒降低到无法检测的水平。然而，HIV 相关神经认知障碍 (HAND) 的发病率却有所上升。这些症状的范围从神经元功能障碍到细胞死亡。在神经元失调的标志物中，我们引用了突触可塑性和神经元通讯的改变。临床上，这些功能障碍导致神经认知障碍，如学习能力改变和空间记忆丧失，即使在接受 HAART 治疗的患者中，也会导致大脑过早衰老。为了支持这些观察结果，我们表明，gp120 蛋白会使 miR-499-5p 及其下游靶标钙调神经磷酸酶 (CaN) 蛋白失活。gp120 蛋白还会促进神经元内钙离子 (Ca) 和活性氧 (ROS) 的积累，导致 CaN 激活和 miR-499-5p 抑制。gp120 蛋白还会导致线粒体碎片化以及形状和大小的改变。使用模拟 miR-499 恢复了线粒体的功能、形态和大小。这些结果表明，gp120 蛋白通过 miR-499-5p/钙调神经磷酸酶途径对神经元产生了额外的影响。
