Effect of VCP modulators on gene expression profiles of retinal ganglion cells in an acute injury mouse model
Effect of VCP modulators on gene expression profiles of retinal ganglion cells in an acute injury mouse model
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DOI：
10.1038/s41598-020-61160-6
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发表时间：
2020-03-06
影响因子：
4.6
通讯作者：
Tsujikawa, Akitaka
中科院分区：
文献类型：
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作者：
Hasegawa, Tomoko;Ikeda, Hanako Ohashi;Tsujikawa, Akitaka
在青光眼中，视网膜神经节细胞受损，导致视野的进行性收缩。我们之前已经证明，京都大学物质（KUS）121和KUS187可以预防青光眼动物模型中视网膜神经节细胞的死亡，包括n-甲基- d -天冬氨酸（NMDA）诱导的神经毒性。KUSs似乎通过维持ATP水平来避免内质网（ER）应激，从而保护神经节细胞免于细胞死亡。为了进一步阐明KUSs的保护机制，我们检测了受影响神经节细胞的基因表达谱。我们首先给kus处理的小鼠注射NMDA，然后用荧光激活细胞分选分离受影响的视网膜神经节细胞。使用下一代测序仪定量细胞中的基因表达。结果，我们发现KUS121上调了几个参与能量代谢的基因。此外，我们还观察到Zfp667的上调，据报道，Zfp667可以抑制凋亡相关基因，防止细胞死亡。这些结果进一步支持了KUS121作为一种保护视网膜神经节细胞的治疗药物在青光眼等眼科疾病中的适用性。
In glaucoma, retinal ganglion cells are damaged, leading to the progressive constriction of the visual field. We have previously shown that the valosin-containing protein (VCP) modulators, Kyoto University Substance (KUS)121 and KUS187, prevent the death of retinal ganglion cells in animal models of glaucoma, including the one generated by N-methyl-D-aspartate (NMDA)-induced neurotoxicity. KUSs appeared to avert endoplasmic reticulum (ER) stress by maintaining ATP levels, resulting in the protection of ganglion cells from cell death. To further elucidate the protective mechanisms of KUSs, we examined gene expression profiles in affected ganglion cells. We first injected KUS-treated mice with NMDA and then isolated the affected retinal ganglion cells using fluorescence-activated cell sorting. Gene expression in the cells was quantified using a next-generation sequencer. Resultantly, we found that KUS121 upregulated several genes involved in energy metabolism. In addition, we observed the upregulation of Zfp667, which has been reported to suppress apoptosis-related genes and prevent cell death. These results further support the suitability of KUS121 as a therapeutic drug in protecting retinal ganglion cells in ophthalmic disorders, such as glaucoma.