Beijing Institute for Neuroscience, Department of Neurobiology, Capital Medical University, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing 100069, China.
Int J Biochem Cell Biol. 2011 May;43(5):732-41. doi: 10.1016/j.biocel.2011.01.014. Epub 2011 Feb 15.
α-Synuclein (α-syn), a protein involved in the pathogenesis of Parkinson's disease (PD), is known to accumulate in mitochondria, disrupt mitochondrial function. However, the molecular mechanisms that link these pathological responses have not been investigated. In rats overexpressing α-syn in the substantia nigra (SN) through adeno-associated virus (AAV) transduction, about 50% of tyrosine hydroxylase positive neurons were lost after 24 weeks. Overexpression of α-syn was also associated with morphological deformation of mitochondria and depolarization of the mitochondrial membrane potential (ΔΨm). Both co-immunoprecipitation and confocal microscopy demonstrated that mitochondrial α-syn associated with adenylate translocator (ANT), a component of the mitochondrial permeability transition pore (mPTP). The depolarization of ΔΨm was partially reversed in vitro by bongkrekic acid (BKA), an inhibitor of ANT, suggesting that the molecular association between α-syn and ANT facilitated ΔΨm depolarization. Concomitant with α-syn accumulation in mitochondria, abnormal mitochondrial morphology, ΔΨm depolarization, and loss of TH-positive neurons, there was a decrease in apoptosis-inducing factor (AIF) within the mitochondrial matrix, suggesting possible translocation to the cytosol. Our findings suggest that overexpression of α-syn may cause mitochondrial defects in dopaminergic neurons of the substantia nigra through an association with adenylate translocator and activation of mitochondria-dependent cell death pathways. Disruption of normal mitochondrial function may contribute to the loss of dopaminergic neurons in Parkinson's disease.
α-突触核蛋白（α-syn）是一种参与帕金森病（PD）发病机制的蛋白质，已知其在细胞内聚积在 线粒体 中，破坏线粒体功能。然而，将这些病理反应联系起来的分子机制尚未被研究。在通过腺相关病毒（AAV）转导过表达 α-syn 的 黑质 （SN）大鼠中，约 50%的酪氨酸羟化酶阳性神经元在 24 周后丢失。α-syn 的过表达还与线粒体形态变形和线粒体膜电位（ΔΨm）去极化有关。共免疫沉淀和共聚焦显微镜显示，线粒体 α-syn 与腺嘌呤核苷酸转位酶（ANT）结合，ANT 是线粒体通透性转换孔（mPTP）的组成部分。在体外，ANT 的抑制剂 苯并克酮酸（BKA）部分逆转了 ΔΨm 的去极化，这表明 α-syn 和 ANT 之间的分子结合促进了 ΔΨm 的去极化。与线粒体中 α-syn 的积累、线粒体形态异常、ΔΨm 去极化以及 TH 阳性神经元的丧失同时发生的是，线粒体基质中的凋亡诱导因子（AIF）减少，这表明 AIF 可能向细胞质易位。我们的研究结果表明，α-syn 的过表达可能通过与腺嘌呤核苷酸转位酶结合并激活线粒体依赖性细胞死亡途径，导致黑质多巴胺能神经元中的线粒体缺陷。正常线粒体功能的破坏可能导致帕金森病中多巴胺能神经元的丧失。
