The study of modulation of neuronal cell death and searching for new functional molecule regulated by endoplasmic reticulum stress and by innate immune system

最近的研究表明，神经退行性疾病，如阿尔茨海默氏病和帕金森氏病涉及内质网（ER）功能的破坏。我们研究了4-苯基丁酸酯（4-PBA）对帕金森相关内皮素受体样受体（Pael-R）蓄积的影响，Pael-R与常染色体隐性遗传性青少年帕金森综合征（AR-JP）多巴胺能神经元的丢失病理相关。4-PBA可恢复Paer-R蛋白的正常表达，抑制Paer-R积累引起的内质网应激。此外，我们发现，4-PBA衰减ER应激诱导的信号转导通路的激活和随后的神经元细胞死亡。此外，我们还发现4-PBA在体外具有化学伴侣活性，可以阻止变性α-乳白蛋白和牛血清白蛋白（BSA）的聚集。流行病学证据表明，非甾体抗炎药（NSAIDs）可以降低帕金森病和阿尔茨海默病的风险。然而，NSAID引起其抗神经变性作用的机制尚不清楚。我们发现，阿司匹林预处理显着抑制衣霉素诱导的ER应激反应，如XBP-1 mRNA剪接和诱导GRP 78和CHOP。此外，我们证明了aspinin直接抑制还原α-乳白蛋白和BSA的聚集，表明阿司匹林作为化学伴侣的可能性。

Recent studies have shown that neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are involved in a disruption of endoplasmic reticulum (ER) function. We investigated the effects of 4-phenylbutylate (4-PBA) on the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R) pathologically relevant to the loss of dopaminergic neurons in autosomal recessive juvenile Parkinsonism (AR-JP). 4-PBA restored the normal expression of Paer-R protein and suppressed ER stress induced by the accumulation of Paer-R. In addition, we showed that 4-PBA attenuated the activation of ER-stress-induced signal transduction pathways and subsequent neuronal cell death. Furthermore, we revealed that 4-PBA possesses chemical chaperon activity in vitro, which prevents the aggregation of denatured α-lactalbumin and bovine serum albumin (BSA).Epidemiological evidence has shown that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of Parkinson's disease and Alzheimer's disease. However, the mechanism (s) by which NSAIDs elicit their anti-neurodegenerative effects is not clear. We found that pretreatment with aspirin significantly inhibited tunicamycin-induced ER-stress response such as XBP-1 mRNA splicing and induction of GRP78 and CHOP. Furthermore, we demonstrated that aspinin directly inhibited the aggregation of reduced α-lactalbumin and BSA, indicating the possibility that aspirin act as a chemical chaperone.