Itakura Masanori, Kubo Takeya, Kaneshige Akihiro, Nakatsuji Masatoshi, Harada Naoki, Yamaji Ryoichi, Hikida Takatoshi, Inui Takashi, Nakajima Hidemitsu
Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku Ourai Kita, Izumisano, Osaka 598-8531, Japan.
Laboratory of Biological Macromolecules, Graduate School of Agriculture, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
iScience. 2025 May 2;28(6):112564. doi: 10.1016/j.isci.2025.112564. eCollection 2025 Jun 20.
Neuronal death in acute ischemic stroke (AIS) is largely caused by the neurotoxic mechanism of oxidative/nitrosative stress, which is responsible for ischemia-reperfusion injury. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein that mediates cell death under oxidative/nitrosative stress. The active site of GAPDH, residue cysteine-152 (Cys-152), is oxidized and forms intermolecular disulfide bonds that induce GAPDH aggregation, which causes mitochondrial dysfunction and eventually leads to cell death. A GAPDH-C152A mutant dominant-negatively suppresses GAPDH aggregation. Herein, we report that neuron-specific expression of GAPDH-C152A in conditional transgenic mice decreased GAPDH aggregation and brain damage induced by ischemia-reperfusion injury in an AIS mouse model. Furthermore, GAPDH aggregation inhibitor peptide-17, developed by our peptide-screening-methods, ameliorated brain infarction and neurological deficits, even after 6 h of reperfusion. These findings suggest that inhibition of GAPDH aggregation may be a potential therapeutic target for AIS. Further efforts are warranted to translate these findings to treatment with AIS.
急性缺血性中风（AIS）中的神经元死亡主要由氧化/亚硝化应激的神经毒性机制引起，该机制导致缺血再灌注损伤。甘油醛-3-磷酸脱氢酶（GAPDH）是一种多功能蛋白，在氧化/亚硝化应激下介导细胞死亡。GAPDH的活性位点，即半胱氨酸-152（Cys-152）残基，被氧化并形成分子间二硫键，诱导GAPDH聚集，进而导致线粒体功能障碍并最终导致细胞死亡。GAPDH-C152A突变体以显性负性方式抑制GAPDH聚集。在此，我们报告在条件转基因小鼠中神经元特异性表达GAPDH-C152A可减少AIS小鼠模型中缺血再灌注损伤诱导的GAPDH聚集和脑损伤。此外，我们通过肽筛选方法开发的GAPDH聚集抑制剂肽-17，即使在再灌注6小时后，也能改善脑梗死和神经功能缺损。这些发现表明抑制GAPDH聚集可能是AIS的一个潜在治疗靶点。有必要进一步努力将这些发现转化为AIS的治疗方法。
