Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide
Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide
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DOI：
10.1016/s0361-9230(02)00948-6
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发表时间：
2003-02-15
影响因子：
3.8
通讯作者：
Yang, AJ
中科院分区：
文献类型：
--
作者：
Ditaranto-Desimone, K;Saito, M;Yang, AJ
据报道，内体/溶酶体功能受损是几种年龄相关神经系统疾病（如阿尔茨海默病）的一些最早期变化。溶酶体系统的失调也伴随着年龄相关色素的积累，最近的几份报告表明，这种年龄相关的脂褐素积累可以使细胞对氧化应激和凋亡性细胞死亡敏感。在这项研究中，我们已经建立并评估了一个体外年龄相关的病理模式，模型脂褐素积累。我们的模型包括用亲溶酶体洗涤剂处理培养的原代小鼠神经元。我们已经观察到，与亲溶酶体洗涤剂诱导的膜不稳定性相关的最早的生化变化之一是内体/溶酶体质子梯度完整性的丧失，随后是扩大的内体/溶酶体囊泡内鞘磷脂水解和神经酰胺积累的激活。此外，我们证明，神经酰胺积累与近端半胱天冬酶-8和-9以及远端半胱天冬酶-3的激活相关，在细胞死亡出现之前。两者合计，我们建议，干扰的内体/溶酶体系统，除了激活的鞘磷脂酶水解周期，有丝分裂后的神经元老化的过程中发挥重要作用。在病理性衰老过程中，未消化的脂质和蛋白质在功能失调的内体/溶酶体囊泡群体内的异常积累可能是与下游神经变性相关的细胞死亡程序的触发因素。(C)2002年爱思唯尔科技有限公司All rights reserved.
Impairment of endosomal/lysosomal functions are reported as some of the earliest changes in several age-related neurological disorders such as Alzheimer's disease. Dysregulation of the lysosomal system is also accompanied by the accumulation of age-associated pigments and several recent reports have indicated that this age-related lipofuscin accumulation can sensitize cells to oxidative stress and apoptotic cell death. In this study, we have established and evaluated an in vitro age-related pathology paradigm that models lipofuscin accumulation. Our model consists of the treatment of cultured primary mouse neurons with lysosomotropic detergents. We have observed that one of the earliest biochemical changes associated with lysosomotropic detergent-induced membrane instability is a loss of the endosomal/lysosomal proton gradient integrity, followed by an activation of sphingomyelin hydrolysis and ceramide accumulation within enlarged endosomal/lysosomal vesicles. In addition, we demonstrate that ceramide accumulation correlates with the activation of proximal procaspases-8 and -9 as well as distal caspase-3, prior to the appearance of cell death. Taken together, we propose that disturbances of the endosomal/lysosomal system, in addition to the activation of the sphingomyelinase hydrolysis cycle, play essential roles in the course of post-mitotic neuronal aging. The abnormal accumulation of undigested lipids and proteins within dysfunctional endosomal/lysosomal vesicle populations during the process of pathological aging may serve as triggers of the cell death programs that are associated with downstream neurodegeneration. (C) 2002 Elsevier Science Inc. All rights reserved.