Department of Biotechnology, Inter University Centre for Genomics and Gene Technology, University of Kerala, Thiruvananthapuram, 695 581, India.
Department of Botany, University of Kerala, Thiruvananthapuram, 695 581, India.
Genes Genomics. 2022 Dec;44(12):1565-1576. doi: 10.1007/s13258-022-01256-7. Epub 2022 May 14.
The pathophysiology of neurodegenerative diseases (NDDs) is closely associated with cellular oxidative stress which can result in the accumulation of toxic proteins in the endoplasmic reticulum (ER) leading to ER stress and subsequent unfolded protein response (UPR) signaling, a mechanism that aggravate these disorders. Vitamin D has been suggested to have important neuroprotective role and its administration has been shown to reduce neuronal injury, neurotoxicity and oxidative stress in various animal systems.
The current study was undertaken to examine the effect of vitamin D on UPR in ER stress induced Mus musculus neuronal cells.
Mus musculus cortical and hippocampal primary neuronal cultures were pretreated with 1,25-dihydroxyvitamin D (1, 25-(OH)D), the active form of vitamin D, followed by ER stress induction with a chemical ER stress inducer thapsigargin and with an advanced glycated protein, AGE-BSA. The UPR genes and related microRNAs (miRNA) expressions were analyzed mainly using real-time PCR.
The experiment resulted in the suppression of ER stress marker BiP and UPR pathway genes such as Perk, Ire1α, Chop and Puma which mediate cellular apoptosis indicating the protective effect of 1, 25-(OH)D against neuronal ER stress. Further studies into the molecular aspects showed that ER stress mediated down-regulated expression of microRNAs (miRNAs) such as mmu-miR-24, 27b, 124, 224, 290, 351 and 488 which are known to regulate the UPR pathway genes were also reduced with vitamin pretreatment, of which the miRNAs miR-24 and 27b which shares the same cluster are potentially involved in various human diseases.
This study emphasizes the therapeutic role of vitamin D in reducing neuronal ER stress and the need for maintaining sufficient amount of this vitamin in our diet.
神经退行性疾病（NDD）的病理生理学与细胞氧化应激密切相关，氧化应激可导致内质网（ER）中有毒蛋白质的积累，导致 ER 应激和随后的未折叠蛋白反应（UPR）信号转导，这一机制加剧了这些疾病。维生素 D 具有重要的神经保护作用，其给药已被证明可减少各种动物系统中的神经元损伤、神经毒性和氧化应激。
本研究旨在研究维生素 D 对 ER 应激诱导的 Mus musculus 神经元细胞 UPR 的影响。
用 1,25-二羟维生素 D（1,25-（OH）D）预处理 Mus musculus 皮质和海马原代神经元培养物，1,25-（OH）D 是维生素 D 的活性形式，然后用化学 ER 应激诱导剂他普西格雷和晚期糖基化终产物 BSA（AGE-BSA）诱导 ER 应激。主要采用实时 PCR 分析 UPR 基因和相关 microRNAs（miRNA）表达。
实验结果抑制了 ER 应激标志物 BiP 和 UPR 途径基因的表达，如 Perk、Ire1α、Chop 和 Puma，这些基因介导细胞凋亡，表明 1,25-（OH）D 对神经元 ER 应激具有保护作用。进一步的分子研究表明，ER 应激介导的下调表达 microRNAs（miRNAs），如 mmu-miR-24、27b、124、224、290、351 和 488，这些 miRNAs 已知调节 UPR 途径基因，也随着维生素预处理而减少，其中 miRNA miR-24 和 27b 共享同一簇，可能涉及多种人类疾病。
本研究强调了维生素 D 在减少神经元 ER 应激中的治疗作用，并需要在饮食中维持足够的这种维生素。
