TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS

When mutant superoxide dismutase 1 (SOD1) was first linked to amyotrophic lateral sclerosis (ALS), it was thought that ALS is a disease of oxidative stress. Since the discovery of multiple ALS-linked genes involved in RNA processing and proteostasis, most recent research has been focused on molecular defects induced by those mutant genes, but whether and how oxidative stress might contribute to magnification of those molecular defects have remained unaddressed. Strikingly, a hallmark of both familial and sporadic ALS is the aggregation of the essential DNA/RNA binding protein TDP-43, which is thought to cause simultaneous loss-of-nuclear function and gain-of-cytoplasmic toxicity. A central unanswered question is what triggers ALS in adult followed by rapid and irreversible progression? Here we report that neuronal cells are particularly prone to oxidative stress to trigger TDP-43 aggregation, which in turn sponges a large subset of microRNAs and proteins to cause both up-regulation and functional depletion of different sets of gene products. Remarkably, a large fraction of those functionally perturbed genes are nuclear genome-encoded mitochondrial proteins, thus resulting in a global mitochondrial imbalance, which further augments oxidative stress. We propose that this ferocious cycle driven by oxidative stress in combination with causal mutations in critical genes may underlie ALS onset and progression.

当突变型超氧化物歧化酶1（superoxide dismutase 1, SOD1）首次被发现与肌萎缩侧索硬化（amyotrophic lateral sclerosis, ALS）相关时，学界曾认为ALS是一类氧化应激介导的疾病。自多个参与RNA加工与蛋白质稳态的ALS致病基因被鉴定以来，近期绝大多数研究均聚焦于这些突变基因诱导的分子缺陷，但氧化应激是否以及如何参与放大这些分子缺陷，这一问题仍未得到解答。值得注意的是，家族性与散发性ALS的共同标志性病理特征，均为关键DNA/RNA结合蛋白TDP-43的聚集，该过程被认为会同时引发核功能丧失与胞质毒性获得。一个核心且尚未解决的科学问题是：究竟是什么因素触发了成年个体的ALS，并随后引发快速且不可逆的疾病进展？本研究发现，神经元细胞尤其易受氧化应激诱导，进而触发TDP-43聚集；这一聚集过程会作为微小RNA（microRNAs）海绵捕获大量微小RNA与蛋白质，导致多组基因产物的表达上调与功能耗竭同时发生。值得注意的是，其中受功能扰动的基因有很大一部分为核基因组编码的线粒体蛋白，进而引发全局线粒体失衡，进一步加剧氧化应激。我们提出，由氧化应激与关键基因致病突变共同驱动的这一恶性循环，或许是ALS发病与进展的核心病理机制。