The Parkinson's disease gene product DJ-1 modulates miR-221 to promote neuronal survival against oxidative stress.
The Parkinson's disease gene product DJ-1 modulates miR-221 to promote neuronal survival against oxidative stress.
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DOI：
10.1016/j.redox.2018.07.021
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发表时间：
2018-10
期刊：
影响因子：
11.4
通讯作者：
Mouradian MM
中科院分区：
文献类型：
--
作者：
Oh SE;Park HJ;He L;Skibiel C;Junn E;Mouradian MM
DJ-1是一种高度保守的蛋白质，保护神经元免受氧化应激，其功能丧失突变与复发性遗传性帕金森病（PD）有关。虽然许多信号通路已被证明是由DJ-1调节，但其在通过非编码RNA控制细胞存活中的作用仍然知之甚少。在这里，使用微阵列筛选，我们发现敲低人神经母细胞瘤细胞中的DJ-1导致microRNA-221（miR-221）下调。这是人类大脑中最丰富的miRNA之一，并促进神经突生长和神经元分化。然而，将miR-221与遗传形式的PD联系起来的分子机制尚未研究。与微阵列数据一致，miR-221表达在DJ-1-/-小鼠脑中也降低。重新引入野生型DJ-1，而不是其PD连锁致病性M26 I突变体，恢复miR-221表达。值得注意的是，miR-221的过表达对1-甲基-4-苯基吡啶（MPP+）诱导的细胞死亡具有保护作用，而内源性miR-221的抑制使细胞对该毒素敏感。此外，miR-221在基础条件下下调几种促凋亡蛋白的表达，并阻止氧化应激诱导的bcl-2样蛋白11（BIM）的上调。因此，miR-221保护分化的DJ-1敲低的ReNcell VM人多巴胺能神经元细胞免受MPP+诱导的神经突收缩和细胞死亡。DJ-1是促分裂原活化蛋白激酶（MAPK）/细胞外调节激酶（ERK）通路的已知激活剂，并可部分通过该通路调节miR-221水平。我们发现，抑制ERK 1/2可降低miR-221水平，而在DJ-1敲低细胞中过表达ERK 1可增加miR-221水平。这些发现指出了一种新的细胞保护机制，即DJ-1可能通过MAPK/ERK途径增加miR-221的表达，随后导致凋亡分子的抑制。致病性DJ-1突变体无法调节miR-221进一步支持了该机制在神经元健康中的相关性及其在DJ-1相关PD中的失败。
DJ-1 is a highly conserved protein that protects neurons against oxidative stress and whose loss of function mutations are linked to recessively inherited Parkinson's disease (PD). While a number of signaling pathways have been shown to be regulated by DJ-1, its role in controlling cell survival through non-coding RNAs remains poorly understood. Here, using a microarray screen, we found that knocking down DJ-1 in human neuroblastoma cells results in down-regulation of microRNA-221 (miR-221). This is one of the most abundant miRNAs in the human brain and promotes neurite outgrowth and neuronal differentiation. Yet the molecular mechanism linking miR-221 to genetic forms of PD has not been studied. Consistent with the microarray data, miR-221 expression is also decreased in DJ-1-/- mouse brains. Re-introduction of wild-type DJ-1, but not its PD-linked pathogenic M26I mutant, restores miR-221 expression. Notably, over-expression of miR-221 is protective against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death, while inhibition of endogenous miR-221 sensitizes cells to this toxin. Additionally, miR-221 down-regulates the expression of several pro-apoptotic proteins at basal conditions and prevents oxidative stress-induced up-regulation of bcl-2-like protein 11 (BIM). Accordingly, miR-221 protects differentiated DJ-1 knock-down ReNcell VM human dopaminergic neuronal cells from MPP+-induced neurite retraction and cell death. DJ-1 is a known activator of the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) pathway and may modulate miR-221 levels in part through this pathway. We found that inhibiting ERK1/2 decreases miR-221 levels, whereas over-expressing ERK1 in DJ-1 knock-down cells increases miR-221 levels. These findings point to a new cytoprotective mechanism by which DJ-1 may increase miR-221 expression through the MAPK/ERK pathway, subsequently leading to repression of apoptotic molecules. The inability of a pathogenic DJ-1 mutant to modulate miR-221 further supports the relevance of this mechanism in neuronal health and its failure in DJ-1-linked PD.
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