Department of Pharmacology, University of Tartu, Ravila 19, 51014 Tartu, Estonia.
J Biol Chem. 2011 Mar 25;286(12):10814-24. doi: 10.1074/jbc.M110.132514. Epub 2011 Jan 20.
Parkinson disease is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. α-Synuclein accumulation in turn leads to compensatory effects that may include the up-regulation of autophagy. Another common feature of Parkinson disease (PD) is mitochondrial dysfunction. Here, we provide evidence that the overactivation of autophagy may be a link that connects the intracellular accumulation of α-synuclein with mitochondrial dysfunction. We found that the activation of macroautophagy in primary cortical neurons that overexpress mutant A53T α-synuclein leads to massive mitochondrial destruction and loss, which is associated with a bioenergetic deficit and neuronal degeneration. No mitochondrial removal or net loss was observed when we suppressed the targeting of mitochondria to autophagosomes by silencing Parkin, overexpressing wild-type Mitofusin 2 and dominant negative Dynamin-related protein 1 or blocking autophagy by silencing autophagy-related genes. The inhibition of targeting mitochondria to autophagosomes or autophagy was also partially protective against mutant A53T α-synuclein-induced neuronal cell death. These data suggest that overactivated mitochondrial removal could be one of the contributing factors that leads to the mitochondrial loss observed in PD models.
帕金森病的特征是聚集的α-突触核蛋白积累为路易体的主要成分。α-突触核蛋白的积累反过来又导致代偿性效应，可能包括自噬的上调。帕金森病（PD）的另一个常见特征是线粒体功能障碍。在这里，我们提供的证据表明，自噬的过度激活可能是连接α-突触核蛋白的细胞内积累与线粒体功能障碍的一个环节。我们发现，在过表达突变 A53T α-突触核蛋白的原代皮质神经元中，巨自噬的激活导致大量线粒体破坏和丧失，这与能量代谢缺陷和神经元变性有关。当我们通过沉默 Parkin、过表达野生型 Mitofusin 2 和显性负性 Dynamin-related protein 1 抑制线粒体靶向自噬体，或通过沉默自噬相关基因抑制自噬时，没有观察到线粒体的去除或净损失。抑制线粒体靶向自噬体或自噬也部分对突变 A53T α-突触核蛋白诱导的神经元细胞死亡具有保护作用。这些数据表明，过度激活的线粒体去除可能是导致 PD 模型中观察到的线粒体丧失的一个因素。
