MicroRNA-183-5pis stress-inducible and protects neurons against cell death in amyotrophic lateral sclerosis
MicroRNA-183-5pis stress-inducible and protects neurons against cell death in amyotrophic lateral sclerosis
复制标题
MicroRNA-183-5pi 在肌萎缩侧索硬化症中具有应激诱导作用并保护神经元免受细胞死亡
DOI：
10.1111/jcmm.15490
复制
发表时间：
2020-06-18
影响因子：
5.3
通讯作者：
Shang, Huifang
中科院分区：
文献类型：
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作者：
Li, Chunyu;Chen, Yongping;Shang, Huifang
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以运动神经元死亡为特征的致死性神经退行性疾病。ALS的基本发病机制是神经元中的长期细胞应激，其由蛋白质聚集体或活性氧簇的积累引起。然而，压力感知和细胞死亡之间的机制联系尚未确定。在此，我们发现miR-183- 5 p，一种富含神经元的miRNA，在ALS中耦合了应激感受和细胞死亡程序。miR-183- 5 p在神经元中被过氧化氢、衣霉素或TNF-α立即诱导。miR-183- 5 p的过表达增加了应激条件下神经元的存活，而其敲低则导致神经元死亡。miR-183- 5 p通过直接靶向PDCD 4和RIPK 3协调细胞凋亡和坏死凋亡途径，从而保护神经元免受应激条件下的细胞死亡。ALS患者和小鼠模型中miR-183- 5 p的持续减少增强了miR-183- 5 p是应激条件下运动神经元存活的中枢调节因子的观点。我们的研究补充了目前对细胞应激与死亡/存活之间机制联系的理解，并为ALS的临床干预提供了新的靶点。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons. A fundamental pathogenesis of ALS is the prolonged cell stress in neurons, which is caused by either accumulation of protein aggregates or reactive oxygen species. However, the mechanistic link between stress sensing and cell death is unsettled. Here, we identify thatmiR-183-5p, a neuron-enriched miRNA, couples stress sensing and cell death programming in ALS.miR-183-5pis immediately induced by hydrogen peroxide, tunicamycin or TNF-alpha in neurons. The overexpression ofmiR-183-5pincreases neuron survival under stress conditions, whereas its knockdown causes neuron death.miR-183-5pcoordinates apoptosis and necroptosis pathways by directly targetingPDCD4andRIPK3, and thus protects neurons against cell death under stress conditions. The consistent reduction ofmiR-183-5pin ALS patients and mouse models enhances the notion thatmiR-183-5pis a central regulator of motor neuron survival under stress conditions. Our study supplements current understanding of the mechanistic link between cell stress and death/survival, and provides novel targets for clinical interventions of ALS.