Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice.
Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice.
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DOI：
10.1016/j.neuint.2010.08.010
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发表时间：
2010-12
影响因子：
4.2
通讯作者：
Wong, Paul K. Y.
中科院分区：
文献类型：
--
作者：
Kuang, Xianghong;Hu, Wenhui;Yan, Mingshan;Wong, Paul K. Y.
许多神经退行性疾病与中枢神经系统（CNS）细胞中错误折叠蛋白的积累有关。我们以前曾报道，积累的前体包膜蛋白gPr80 env的ts1，莫洛尼鼠白血病病毒（MoMuLV）的突变体，在内质网（ER）的感染的星形胶质细胞，导致ER应激，氧化应激和细胞死亡，随后导致ts1介导的神经退行性病变在感染的小鼠。在本研究中，我们评估了减少ts1感染的星形胶质细胞ER中gPr80env积累的治疗是否对ER应激和细胞死亡具有保护作用。我们发现，苯丁酸（PBA）治疗可以防止未折叠蛋白反应（UPR），ER应激和细胞死亡在培养的ts1感染的星形胶质细胞。PBA的保护作用与其减少gPr80env积累和增加ER中参与蛋白质折叠的蛋白质（如蛋白质二硫键异构酶（PDI）和ERp44）表达的能力相关，而不是通过降低gPr80env的mRNA水平或改变gPr80env的蛋白酶体降解过程。在用PBA治疗的感染小鼠中，我们还注意到脑干组织中神经病理学的严重程度降低，瘫痪的发生延迟。这些结果表明，PBA是一种潜在的有效药物，用于治疗由CNS细胞中蛋白质积累引起的神经变性。
Many neurodegenerative diseases are associated with accumulation of misfolded proteins in cells of the central nervous system (CNS). We have previously reported that accumulation of the precursor envelope protein gPr80env of ts1, a mutant of Moloney murine leukemia virus (MoMuLV), in the endoplasmic reticulum (ER) of infected astrocytes, results in ER stress, oxidative stress and cell death, subsequently leading to ts1-mediated neurodegeneration in infected mice. In the present study, we assessed whether treatments that reduce the accumulation of gPr80env in the ER of ts1-infected astrocytes provided a protective effect against ER stress and cell death. We show that treatment with phenylbutyric acid (PBA) can prevent the unfolded protein response (UPR), ER stress and cell death in cultured ts1-infected astrocytes. The protective effect of PBA is associated with its ability to reduce gPr80env accumulation and to increase the expression of proteins involved in protein folding in the ER, such as protein disulfide isomerase (PDI) and ERp44, rather than by decrease mRNA levels of gPr80env or alter the proteasomal degradation process for gPr80env. In infected mice treated with PBA we also noted a reduction in the severity of the neuropathology in brainstem tissues and a delayed onset of paralysis. These results show that PBA is a potentially effective drug for the treatment of neurodegeneration caused by protein accumulation in cells of the CNS.
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影响因子：
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