Forkhead Box O3a requires BAF57, a subunit of chromatin remodeler SWI/SNF complex for induction of p53 up-regulated modulator of apoptosis (Puma) in a model of Parkinson's disease
Forkhead Box O3a requires BAF57, a subunit of chromatin remodeler SWI/SNF complex for induction of p53 up-regulated modulator of apoptosis (Puma) in a model of Parkinson's disease
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DOI：
10.1111/jnc.14969
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发表时间：
2020-02-05
影响因子：
4.7
通讯作者：
Biswas, Subhas C.
中科院分区：
文献类型：
--
作者：
Sanphui, Priyankar;Das, Anoy Kumar;Biswas, Subhas C.
帕金森病 (PD) 是由于中脑黑质致密部多巴胺能神经元选择性丧失所致。据报道，在多种神经元死亡模式中，转录因子叉头框 O3a (FoxO3a) 被激活并诱导促凋亡蛋白，例如 Bcl-2 相互作用细胞死亡调节剂 (BIM) 和 p53 上调细胞凋亡调节剂 (PUMA)。 FoxO3a 的活性受其控制其亚细胞定位的翻译后修饰的控制。本研究的目的是确定 FoxO3a 是否被激活并上调其促凋亡基因以诱导 PD 中的神经元死亡。我们将神经元 PC12 细胞或多巴胺能神经元的原代培养物暴露于 6-羟基多巴胺 (6-OHDA)，并将 6-OHDA 注入大鼠脑中以开发 PD 模型。我们发现 FoxO3a 经历了多次翻译后修饰，使其响应 6-OHDA 而定位于多巴胺能神经元细胞中。在注入 6-OHDA 的大鼠大脑的多巴胺能神经元中，FoxO3a 的核重新分布也显着增加。此外，FoxO3a 是响应 6-OHDA 的多巴胺能神经变性所必需的，因为 RNAi 介导的 FoxO3a 沉默可以保护这些细胞免受 6-OHDA 毒性。在下游目标的搜索中，我们确定 PUMA 是 FoxO3a 的直接目标。通过敲除 FoxO3a，我们可以成功阻止该模型中促凋亡蛋白 PUMA 的上调。最近，有报道称染色质重塑剂 SWItch/蔗糖不可发酵与 FOXO 结合并激活转录。我们发现 Brg 相关因子 57 (BAF57)（SWItch/蔗糖不可发酵的一个亚类）上调，并在 6-OHDA 诱导的神经元死亡中发挥必要的作用。此外，在这种 PD 细胞模型中，FoxO3a 诱导 PUMA 是必需的。综上所述，我们的研究表明，在染色质重塑剂 BAF57 存在的情况下，FoxO3a 被激活，易位到细胞核，诱导其促凋亡靶标 PUMA，从而在 PD 细胞模型中执行神经元死亡。
Parkinson's disease (PD) results from the selective loss of dopaminergic neurons of substantia nigra pars compacta region of the midbrain. It has been reported that the transcription factor forkhead Box O3a (FoxO3a) is activated and induces pro-apoptotic protein such as Bcl-2-interacting mediator of cell death (BIM) and p53 up-regulated modulator of apoptosis (PUMA) in variety of neuron death paradigms. Activity of FoxO3a is governed by its post-translational modifications which control its subcellular localization. Aim of this study was to determine whether FoxO3a is activated and up-regulates its pro-apoptotic genes to induce neuron death in PD. We exposed neuronal PC12 cells or primary cultures of dopaminergic neurons to 6-hydroxy dopamine (6-OHDA) and infused 6-OHDA in rat brain to develop PD models. We found that FoxO3a undergoes multiple post-translational modifications which render its nuclear localization in dopaminergic neuronal cells in response to 6-OHDA. The nuclear redistribution of FoxO3a is significantly increased in dopaminergic neurons of 6-OHDA infused rat brains as well. Moreover, FoxO3a is required for dopaminergic neurodegeneration in response to 6-OHDA as RNAi-mediated silencing of FoxO3a protects these cells from 6-OHDA toxicity. In a search of the downstream targets we identified PUMA as a direct target of FoxO3a. By knocking down FoxO3a we could successfully block the up-regulation of the pro-apoptotic protein PUMA in this model. Recently, it has been reported that chromatin remodeler SWItch/sucrose non-fermentable binds to FOXO and activates transcription. We found that Brg-associated factor 57 (BAF57), a subclass of SWItch/sucrose non-fermentable is up-regulated and play a necessary role in neuron death induced by 6-OHDA. Moreover, it is required for induction of PUMA by FoxO3a in this cellular model of PD. Taken together, our study suggest that FoxO3a is activated, translocates to nucleus, induces its pro-apoptotic target PUMA in the presence of chromatin remodeler BAF57 to execute neuron death in cellular models of PD.