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Regulation of Neuronal Cell Cycle and Apoptosis by MicroRNA 34a

机译:MicroRNA 34a对神经元细胞周期和细胞凋亡的调节

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The cell cycle of neurons remains suppressed to maintain the state of differentiation and aberrant cell cycle reentry results in loss of neurons, which is a feature in neurodegenerative disorders like Alzheimer's disease (AD). Present studies revealed that the expression of microRNA 34a (miR-34a) needs to be optimal in neurons, as an aberrant increase or decrease in its expression causes apoptosis. miR-34a keeps the neuronal cell cycle under check by preventing the expression of cyclin D1 and promotes cell cycle arrest. Neurotoxic amyloid β1–42 peptide (Aβ42) treatment of cortical neurons suppressed miR-34a, resulting in unscheduled cell cycle reentry, which resulted in apoptosis. The repression of miR-34a was a result of degradation of TAp73, which was mediated by aberrant activation of the MEK extracellular signal-regulated kinase (ERK) pathway by Aβ42. A significant decrease in miR-34a and TAp73 was observed in the cortex of a transgenic (Tg) mouse model of AD, which correlated well with cell cycle reentry observed in the neurons of these animals. Importantly, the overexpression of TAp73α and miR-34a reversed cell cycle-related neuronal apoptosis (CRNA). These studies provide novel insights into how modulation of neuronal cell cycle machinery may lead to neurodegeneration and may contribute to the understanding of disorders like AD.
机译:神经元的细胞周期保持被抑制以维持分化状态,异常的细胞周期再进入导致神经元的丧失,这是神经退行性疾病如阿尔茨海默氏病(AD)的特征。目前的研究表明,microRNA 34a(miR-34a)的表达需要在神经元中达到最佳,因为其表达的异常增加或减少会导致细胞凋亡。 miR-34a通过阻止细胞周期蛋白D1的表达来控制神经细胞周期,并促进细胞周期停滞。皮质神经元的神经毒性淀粉样蛋白β 1-42 肽(Aβ 42 )处理可抑制miR-34a,导致非计划的细胞周期再进入,从而导致细胞凋亡。 miR-34a的抑制是TAp73降解的结果,它是由Aβ 42 激活MEK细胞外信号调节激酶(ERK)途径介导的。在AD转基因(Tg)小鼠模型的皮层中观察到miR-34a和TAp73的显着降低,这与在这些动物的神经元中观察到的细胞周期折返密切相关。重要的是,TAp73α和miR-34a的过表达逆转了细胞周期相关的神经元凋亡(CRNA)。这些研究为神经元细胞周期机制的调节如何导致神经退行性变和可能有助于理解AD等疾病提供了新颖的见解。

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