Genetic inhibition of collapsin response mediator protein‐2 phosphorylation ameliorates retinal ganglion cell death in normal‐tension glaucoma models
Genetic inhibition of collapsin response mediator protein‐2 phosphorylation ameliorates retinal ganglion cell death in normal‐tension glaucoma models
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DOI：
10.1111/gtc.12971
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发表时间：
2022-06
期刊：
影响因子：
2.1
通讯作者：
Musukha Mala Brahma;Kazuya Takahashi;K. Namekata;T. Harada;Y. Goshima;T. Ohshima
中科院分区：
文献类型：
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作者：
Musukha Mala Brahma;Kazuya Takahashi;K. Namekata;T. Harada;Y. Goshima;T. Ohshima
青光眼是由视网膜神经节细胞（RGC）死亡引起的神经退行性疾病。青光眼的病因有哪些？然而，青光眼通常在正常IOP下发展，称为正常眼压性青光眼（NTG）。谷氨酸神经毒性被认为是NTG的重要原因之一，导致通过N-甲基-D-天冬氨酸（NMDA）受体过度刺激视网膜神经元。本研究检测了神经元蛋白反应介导蛋白-2（CRMP 2）的磷酸化，CRMP 2是一种在神经元中大量表达并参与其发育的蛋白质。在两种小鼠模型中，NMDA注射和谷氨酸/天冬氨酸转运蛋白（GLAST）突变体，RGC中细胞周期蛋白依赖性激酶5（Cdk 5）位点的CRMP 2磷酸化升高。我们证实，在CRMP 2磷酸化受到遗传抑制的CRMP 2KI/KI小鼠中，NMDA给药后可以抑制RGCs数量和视网膜内层（IRL）厚度的减少。接下来，我们研究了GLAST杂合子（GLAST+/−）与CRMP 2KI/KI（GLAST+/−; CRMP 2KI/KI）以及GLAST敲除（GLAST−/−）小鼠与CRMP 2KI/KI（GLAST −/−; CRMP 2KI/KI）小鼠，并将它们与GLAST+/−和GLAST−/−小鼠进行比较。pCRMP 2（S522）抑制显著减少RGC损失和IRL变薄。这些结果表明，抑制CRMP 2磷酸化可能是治疗NTG的新策略。
Glaucoma is a neurodegenerative disorder caused by the death of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is a cause of glaucoma. However, glaucoma often develops with normal IOP and is known as normal‐tension glaucoma (NTG). Glutamate neurotoxicity is considered as one of the significant causes of NTG, resulting in excessive stimulation of retinal neurons via the N‐methyl‐D‐aspartate (NMDA) receptors. The present study examined the phosphorylation of collapsin response mediator protein‐2 (CRMP2), a protein that is abundantly expressed in neurons and involved in their development. In two mouse models, NMDA‐injection and glutamate/aspartate transporter (GLAST) mutant, CRMP2 phosphorylation at the cyclin‐dependent kinase‐5 (Cdk5) site was elevated in RGCs. We confirmed that the decrease in the number of RGCs and thickness of the inner retinal layer (IRL) could be suppressed after NMDA administration in CRMP2KI/KI mice with genetically inhibited CRMP2 phosphorylation. Next, we investigated GLAST heterozygotes (GLAST+/−) with CRMP2KI/KI (GLAST+/−;CRMP2KI/KI) and GLAST knockout (GLAST−/−) mice with CRMP2KI/KI (GLAST−/−;CRMP2KI/KI) mice and compared them with GLAST+/− and GLAST−/− mice. pCRMP2 (S522) inhibition significantly reduced RGC loss and IRL thinning. These results suggest that the inhibition of CRMP2 phosphorylation could be a novel strategy for treating NTG.