Department of Biology Yonsei University College of Life Science and Biotechnology, Seoul 120-749, South Korea.
Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S162-6. doi: 10.1016/S1353-8020(13)70039-7.
Autophagy is an evolutionarily conserved process that mediates the degradation of abnormal proteins and the removal of dysfunctional organelles. Recently, accumulating evidence has implicated the dysregulation of autophagy as underlying the pathophysiology of several neurodegenerative diseases. Using culture models of Parkinson's disease, we have investigated whether and how prototypic autophagic events occur upon exposure to N-methyl-4-phenylpyridinium, a dopaminergic neurotoxin, or nigericin, a K(+)/H(+) ionophore. From these independent studies, we have found that these drugs equally induce morphological and biochemical changes typical of autophagy, including accumulation of autophagic vacuoles, appearance of LC3-II forms, and alteration in the expression and distribution of p62. Further investigation has indicated that drug-induced autophagic phenomena are largely the consequences of an impaired autophagic flux. In these cell death paradigms, we have intriguingly found that Bak, a prototypic proapoptotic protein of the Bcl-2 family, exerts a protective role via reduction of the area occupied by swollen vacuoles and appearance of the LC3-II form, whereas silencing of Bak aggravates these phenomena. Further study has indicated that a protective role for Bak is primarily ascribed to its regulatory effect on the maintenance of autophagic flux and vacuole homeostasis. In this regard, a regulatory role for calcium has been proposed.
自噬是一种进化上保守的过程，介导异常蛋白质的降解和功能失调的细胞器的清除。最近，越来越多的证据表明自噬的失调是几种神经退行性疾病的病理生理学基础。我们使用帕金森病的培养模型，研究了暴露于多巴胺能神经毒素 N-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）或钾离子/氢离子载体 Nigericin 时，自噬是否以及如何发生。从这些独立的研究中，我们发现这些药物同样诱导了自噬的形态和生化变化，包括自噬小体的积累、LC3-II 形式的出现以及 p62 的表达和分布的改变。进一步的研究表明，药物诱导的自噬现象主要是由于自噬通量受损的结果。在这些细胞死亡模型中，我们令人惊讶地发现，Bak，一种 Bcl-2 家族的典型促凋亡蛋白，通过减少肿胀小泡的面积和 LC3-II 形式的出现，发挥保护作用，而 Bak 的沉默则加重了这些现象。进一步的研究表明，Bak 的保护作用主要归因于其对维持自噬通量和小泡动态平衡的调节作用。在这方面，已经提出了钙的调节作用。
