Marzullo Marta, Romano Giulia, Pellacani Claudia, Riccardi Federico, Ciapponi Laura, Feiguin Fabian
Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, 00185, Roma, Italy.
Dipartimento di Biologia e Biotecnologie "C. Darwin", Sapienza Università di Roma, 00185, Roma, Italy.
Cell Death Discov. 2023 Sep 27;9(1):357. doi: 10.1038/s41420-023-01643-3.
Aging progressively modifies the physiological balance of the organism increasing susceptibility to both genetic and sporadic neurodegenerative diseases. These changes include epigenetic chromatin remodeling events that may modify the transcription levels of disease-causing genes affecting neuronal survival. However, how these events interconnect is not well understood. Here, we found that Su(var)3-9 causes increased methylation of histone H3K9 in the promoter region of TDP-43, the most frequently altered factor in amyotrophic lateral sclerosis (ALS), affecting the mRNA and protein expression levels of this gene through epigenetic modifications that appear to be conserved in aged Drosophila brains, mouse, and human cells. Remarkably, augmented Su(var)3-9 activity causes a decrease in TDP-43 expression followed by early defects in locomotor activities. In contrast, decreasing Su(var)3-9 action promotes higher levels of TDP-43 expression, improving motility parameters in old flies. The data uncover a novel role of this enzyme in regulating TDP-43 expression and locomotor senescence and indicate conserved epigenetic mechanisms that may play a role in the pathogenesis of ALS.
衰老会逐渐改变机体的生理平衡，增加对遗传性和散发性神经退行性疾病的易感性。这些变化包括表观遗传染色质重塑事件，这些事件可能会改变影响神经元存活的致病基因的转录水平。然而，这些事件之间是如何相互联系的，目前还不太清楚。在这里，我们发现Su(var)3-9会导致TDP-43启动子区域组蛋白H3K9甲基化增加，TDP-43是肌萎缩侧索硬化症（ALS）中最常发生改变的因子，通过表观遗传修饰影响该基因的mRNA和蛋白质表达水平，而这些表观遗传修饰在衰老的果蝇大脑、小鼠和人类细胞中似乎是保守的。值得注意的是，Su(var)3-9活性增强会导致TDP-43表达下降，随后出现运动活动早期缺陷。相反，降低Su(var)3-9的作用会促进TDP-43表达水平升高，改善老年果蝇的运动参数。这些数据揭示了这种酶在调节TDP-43表达和运动衰老中的新作用，并表明保守的表观遗传机制可能在ALS的发病机制中起作用。
