Significance of the Autophagy Pathway after Traumatic Brain Injury

On the basis of the fact that autophagy is a selfdefense mechanism for surviving environmental

stress (Moore et al, 2006), activation of autophagy pathway is probably a neuroprotective response after TBI. To survive extreme environmental conditions or accidents such as TBI, neurons must make use of all available defense mechanisms to cope with accumulation of abnormal cellular structuresafter injury. Upregulation of the autophagy pathway,the chief machinery for bulk degradation of aberrant organelles, should be responsible for eliminating TBI-generated aberrant components to maintain neuronal homeostasis. Although ATG gene knockout studies have clearly shown that the autophagy plays a key role in protecting neurons from protein aggregationinduced injury, in theory overactivation of autophagy might also carry potential risks. For example, overcrowded lysosomes might leak their hydrolases causing secondary cell injury. Autophagy has also been proposed to take part in cell death, the socalled"autophagic cell death". Autophagic cell death has been suggested as a new mode of cell death distinct from both apoptosis and necrosis, and it is characterized by cytoplasmic accumulation of autophagic compartments (Swanson, 2006). Currently, it remains much controversial whether autophagic cell death is a tissue injury-accompanied epiphenomenon caused by an unsuccessful autophagic attempt to rescue dying cells or it is a programmed cell death response (Swanson, 2006). Several studies using chemical inhibitors of autophagy have led to inconclusive evidence, owing to the nonspecific properties of these inhibitors (Nixon,2006; Klionsky, 2006). However, growing lines of evidence support the view that autophagy is essential for maintaining neuronal homeostasis: (i) deficiency in this pathway leads to neurodegenerationand human genetic diseases (Eskelinen, 2006; Nishino, 2006) and (ii) conditional knockout of key autophagic genes, ATG5 or ATG7, leads to accumulation of intracellular protein aggregates and neuronal death (Komatsu et al, 2006; Hara et al, 2006).Therefore, in most circumstances, induction of the autophagy pathway may be a cell protective response, and it is inadequate or defective autophagy, rather than excessive autophagy, that promotes neuronal death (Nixon, 2006). Future studies will determine whether and how manipulation of the autophagy pathway improves post-TBI recovery.

外伤性脑损伤后自噬途径的重要性

   自噬是一种在环境应激状态下生存的自我保护机制，TBI之后自噬机制的激活可能是一个神经保护反应。为了在极端环境条件或意外事件如TBI后存活，神经元必须充分利用各种防护机制去应对那些损伤所留下的异常细胞结构。外伤性脑损伤发生后,自噬途径的上调是消除大量异常细胞器官，维持动态稳定的重要作用机制。虽然ATG基因敲除研究已清楚显示，自噬对受损蛋白聚集诱导的神经元保护中起着关键作用，但在理论上，过度激活的自噬也可能有潜在危险，例如过多的溶酶体可泄露它们的水解酶导致细胞的次生伤害。自噬也被提出参与了细胞死亡，这被称作自噬细胞死亡。自噬细胞死亡已经被认为是一种新的细胞死亡模式，它明显不同于细胞凋亡与坏死，其特征是自噬隔离舱在胞质中的蓄集。自噬细胞死亡是一种未能成功拯救死亡细胞所导致的组织损伤伴随现象，还是一种程序性细胞死亡反应,现在还有很多争议。由于这些抑制物的非特异性，几个利用自噬化学抑制剂的研究得到了不确定的证据。但是，越来越多的线索支持这个观点：自噬是维持神经动态稳定所必需的。一，这条途径的缺乏将导致神经退行性变及人类遗传疾病；(Eskelinen, 2006; Nishino, 2006) 二，条件性敲除自噬关键基因ATG5 或ATG7，会导致细胞内蛋白聚集体的蓄积和神经死亡。(Komatsu et al, 2006; Hara et al, 2006)；因此，在大多数情况下，自噬途径可能是诱导细胞保护反应。它是局限与不完全的自噬，而不是促进神经死亡的过度自噬。今后的研究将决定自噬途径是否及如何操控外伤性脑损伤后的恢复改善。