Volbracht C, Leist M, Nicotera P
Faculty of Biology, Department of Molecular Toxicology, University of Konstanz, Konstanz, Germany.
Mol Med. 1999 Jul;5(7):477-89.
Early loss of neurites followed by delayed damage of neuronal somata is a feature of several neurodegenerative diseases. Death by apoptosis would ensure the rapid removal of injured neurons, whereas conditions that prevent apoptosis may facilitate the persistence of damaged cells and favor inflammation and disease progression.
Cultures of cerebellar granule cells (CGC) were treated with microtubule disrupting agents. These compounds induced an early degeneration of neurites followed by apoptotic destruction of neuronal somata. The fate of injured neurons was followed after co-exposure to caspase inhibitors or agents that decrease intracellular ATP (deoxyglucose, S-nitrosoglutathione, 1-methyl-4-phenylpyridinium). We examined the implications of energy loss for caspase activation, exposure of phagocytosis markers, and long-term persistence of damaged cells.
In CGC exposed to colchicine or nocodazole, axodendritic degeneration preceded caspase activation and apoptosis. ATP-depleting agents or protein synthesis inhibition prevented caspase activation, translocation of the phagocytosis marker, phosphatidylserine, and apoptotic death. However, they did not affect the primary neurite loss. Repletion of ATP by enhanced glycolysis restored all apoptotic features. Peptide inhibitors of caspases also prevented the apoptotic changes in the cell bodies, although the axodendritic net was lost. Under this condition cell demise still occurred 48 hr later in a caspase-independent manner and involved plasma membrane lysis at the latest stage.
Inhibition of the apoptotic machinery by drugs, energy deprivation, or endogenous mediators may result in the persistence and subsequent lysis of injured neurons. In vivo, this may favor the onset of inflammatory processes and perpetuate neurodegeneration.
神经突早期丧失，随后神经元胞体延迟受损，是几种神经退行性疾病的一个特征。凋亡死亡可确保快速清除受损神经元，而阻止凋亡的情况可能会促进受损细胞的持续存在，并有利于炎症和疾病进展。
用微管破坏剂处理小脑颗粒细胞（CGC）培养物。这些化合物诱导神经突早期退化，随后神经元胞体发生凋亡性破坏。在同时暴露于半胱天冬酶抑制剂或降低细胞内ATP的试剂（脱氧葡萄糖、S-亚硝基谷胱甘肽、1-甲基-4-苯基吡啶）后，观察受损神经元的命运。我们研究了能量损失对半胱天冬酶激活、吞噬作用标志物暴露以及受损细胞长期持续存在的影响。
在暴露于秋水仙碱或诺考达唑的CGC中，轴突树突退化先于半胱天冬酶激活和凋亡。消耗ATP的试剂或蛋白质合成抑制可阻止半胱天冬酶激活、吞噬作用标志物磷脂酰丝氨酸的转位以及凋亡死亡。然而，它们并不影响初级神经突的丧失。通过增强糖酵解补充ATP可恢复所有凋亡特征。半胱天冬酶的肽抑制剂也可阻止细胞体中的凋亡变化，尽管轴突树突网络已丧失。在这种情况下，细胞死亡仍在48小时后以不依赖半胱天冬酶 的方式发生，并且在最晚阶段涉及质膜裂解。
药物、能量剥夺或内源性介质对凋亡机制的抑制可能导致受损神经元的持续存在并随后裂解。在体内，这可能有利于炎症过程的开始并使神经退行性变持续存在。
