The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis
The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis
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DOI：
10.1093/hmg/ddi134
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发表时间：
2005-05-01
影响因子：
3.5
通讯作者：
Yankner, BA
中科院分区：
文献类型：
--
作者：
Xu, J;Zhong, N;Yankner, BA
DJ-1基因突变导致早发性常染色体隐性帕金森病（PD），尽管DJ-1在多巴胺能神经元变性中的作用尚未得到解决。在这里，我们表明，与DJ-1在多巴胺能神经元细胞中的主要相互作用蛋白是核蛋白p54 nrb和嘧啶束结合蛋白相关剪接因子（PSF），转录和RNA代谢的两个多功能调节器。PD相关的DJ-1突变体表现出减少的核分布和增加的线粒体定位，导致与辅激活因子p54 nrb和阻遏物PSF的共定位减少。与致病性DJ-1突变体不同，野生型DJ-1的作用是抑制PSF的转录沉默活性。此外，转录沉默子PSF诱导神经元凋亡，这可以被野生型DJ-1逆转，但在较小程度上被PD相关的DJ-1突变体逆转。DJ-1特异性小干扰RNA使细胞对PSF诱导的凋亡敏感。DJ-1和p54 nrb均阻断氧化应激和突变体α-突触核蛋白诱导的细胞死亡。因此，DJ-1是一种神经保护性转录共激活因子，可能与p54 nrb和PSF协同作用，以调节神经保护性遗传程序的表达。DJ-1的转录辅激活因子功能受损的突变使多巴胺能神经元易于凋亡，并可能导致PD的发病机制。
Mutations in the DJ-1 gene cause early-onset autosomal recessive Parkinson's disease (PD), although the role of DJ-1 in the degeneration of dopaminergic neurons is unresolved. Here we show that the major interacting-proteins with DJ-1 in dopaminergic neuronal cells are the nuclear proteins p54nrb and pyrimidine tract-binding protein-associated splicing factor (PSF), two multifunctional regulators of transcription and RNA metabolism. PD-associated DJ-1 mutants exhibit decreased nuclear distribution and increased mitochondrial localization, resulting in diminished co-localization with co-activator p54nrb and repressor PSF. Unlike pathogenic DJ-1 mutants, wild-type DJ-1 acts to inhibit the transcriptional silencing activity of the PSF. In addition, the transcriptional silencer PSF induces neuronal apoptosis, which can be reversed by wild-type DJ-1 but to a lesser extent by PD-associated DJ-1 mutants. DJ-1-specific small interfering RNA sensitizes cells to PSF-induced apoptosis. Both DJ-1 and p54nrb block oxidative stress and mutant alpha-synuclein-induced cell death. Thus, DJ-1 is a neuroprotective transcriptional co-activator that may act in concert with p54nrb and PSF to regulate the expression of a neuroprotective genetic program. Mutations that impair the transcriptional co-activator function of DJ-1 render dopaminergic heurons vulnerable to apoptosis and may contribute to the pathogenesis of PD.