Jayanthi Subramaniam, Deng Xiaolin, Noailles Pierre-Antoine H, Ladenheim Bruce, Cadet Jean Lud
Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institute of Health, DHHS, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA.
FASEB J. 2004 Feb;18(2):238-51. doi: 10.1096/fj.03-0295com.
Methamphetamine (METH) is an illicit drug that causes neurodegenerative effects in humans. In rodents, METH induces apoptosis of striatal glutamic acid decarboxylase (GAD) -containing neurons. This paper provides evidence that METH-induced cell death occurs consequent to interactions of ER stress and mitochondrial death pathways. Specifically, injections of METH are followed by an almost immediate activation of proteases calpain and caspase-12, events consistent with drug-induced ER stress. Involvement of ER stress was further supported by observations of increases in the expression of GRP78/BiP and CHOP. Participation of the mitochondrial pathway was demonstrated by the transition of AIF, smac/DIABLO, and cytochrome c from mitochondrial into cytoplasmic fractions. These changes occur before the apoptosome-associated pro-caspase-9 cleavage. Effector caspases-3 and -6, but not -7, were cleaved with the initial time of caspase-3 activation occurring before caspase 9 cleavage; this suggests possible earlier cleavage of caspase-3 by caspase-12. These events preceded proteolysis of the caspase substrates DFF-45, lamin A, and PARP in nuclear fractions. These findings indicate that METH causes neuronal apoptosis in part via cross-talks between ER- and mitochondria-generated processes, which cause activation of both caspase-dependent and -independent pathways.
甲基苯丙胺（METH）是一种会对人类造成神经退行性影响的非法药物。在啮齿动物中，METH会诱导纹状体中含有谷氨酸脱羧酶（GAD）的神经元发生凋亡。本文提供的证据表明，METH诱导的细胞死亡是内质网应激和线粒体死亡途径相互作用的结果。具体而言，注射METH后，蛋白酶钙蛋白酶和半胱天冬酶-12几乎会立即被激活，这些事件与药物诱导的内质网应激一致。GRP78/BiP和CHOP表达增加的观察结果进一步支持了内质网应激的参与。线粒体途径的参与通过凋亡诱导因子（AIF）、第二线粒体衍生激活因子/直接 IAP 结合蛋白低分子量蛋白（smac/DIABLO）和细胞色素c从线粒体向细胞质部分的转移得到证明。这些变化发生在凋亡小体相关的前半胱天冬酶-9裂解之前。效应半胱天冬酶-3和-6被裂解，但半胱天冬酶-7未被裂解，半胱天冬酶-3的初始激活时间发生在半胱天冬酶9裂解之前；这表明半胱天冬酶-12可能更早地裂解半胱天冬酶-3。这些事件先于核部分中半胱天冬酶底物DNA片段化因子45（DFF-45）、核纤层蛋白A和聚（ADP-核糖）聚合酶（PARP）的蛋白水解。这些发现表明，METH部分通过内质网和线粒体产生的过程之间的相互作用导致神经元凋亡，这会激活半胱天冬酶依赖性和非依赖性途径。
