Ren Jianbing, Yuan Debin, Xie Lili, Tao Xuelei, Duan Chenwei, Bao Yifeng, He Yunfeng, Ge Jianbin, Lu Hongjian
Department of Rehabilitation, the Second People's Hospital of Nantong, Nantong, Jiangsu Province, 226001, China.
Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu Province, 226001, China.
Metab Brain Dis. 2017 Apr;32(2):565-575. doi: 10.1007/s11011-016-9943-6. Epub 2017 Jan 7.
Vps4, vacuolar protein sorting 4, belongs to ATPases Associated with diverse cellular Activities (AAA) protein family which is made up of Vps4A and Vps4B. Previous studies demonstrated that Vps4A plays vital roles in diverse aspects such as virus budding, the efficient transport of H-Ras to the PM (plasma membrane) and the involvement in the MVB (multivesiculate bodies) pathway. Interestingly, Vps4A is also expressed in the brain. However, the distribution and function of Vps4A in ICH diseases remain unclear. In this study, we show that Vps4A may be involved in neuronal apoptosis during pathophysiological processes of intracerebral hemorrhage (ICH). Based on the results of Western blot and immunohistochemistry, we found a remarkable up-regulation of Vps4A expression surrounding the hematoma after ICH. Double labeled immunofluorescence showed that Vps4A was co-expressed with NeuN but rarely with astrocytes and microglia. Morever, we detected that neuronal apoptosis marker active caspase-3 had co-localizations with Vps4A. Additionaly, Vps4A knockdown in vitro specifically leads to decreasing neuronal apoptosis coupled with increased Akt phosphorylation. All datas suggested that Vps4A was involved in promoting neuronal apoptosis via inhibiting Akt phosphorylation after ICH.
Vps4，即液泡蛋白分选蛋白4，属于与多种细胞活动相关的ATP酶（AAA）蛋白家族，该家族由Vps4A和Vps4B组成。先前的研究表明，Vps4A在多个方面发挥着重要作用，如病毒出芽、H-Ras向质膜（PM）的有效转运以及参与多泡体（MVB）途径。有趣的是，Vps4A在大脑中也有表达。然而，Vps4A在脑出血（ICH）疾病中的分布和功能仍不清楚。在本研究中，我们表明Vps4A可能在脑出血（ICH）的病理生理过程中参与神经元凋亡。基于蛋白质免疫印迹和免疫组织化学的结果，我们发现脑出血后血肿周围Vps4A表达显著上调。双标免疫荧光显示Vps4A与NeuN共表达，但很少与星形胶质细胞和小胶质细胞共表达。此外，我们检测到神经元凋亡标志物活性半胱天冬酶-3与Vps4A共定位。另外，体外敲低Vps4A特异性导致神经元凋亡减少，同时Akt磷酸化增加。所有数据表明，脑出血后Vps4A通过抑制Akt磷酸化参与促进神经元凋亡。
