Buck Institute, Novato, CA 94945, USA.
NxCell Science, Novato, CA 94947, USA.
Stem Cell Reports. 2015 May 12;4(5):847-59. doi: 10.1016/j.stemcr.2015.02.019. Epub 2015 Apr 2.
In this study, we used patient-specific and isogenic PARK2-induced pluripotent stem cells (iPSCs) to show that mutations in PARK2 alter neuronal proliferation. The percentage of TH(+) neurons was decreased in Parkinson's disease (PD) patient-derived neurons carrying various mutations in PARK2 compared with an age-matched control subject. This reduction was accompanied by alterations in mitochondrial:cell volume fraction (mitochondrial volume fraction). The same phenotype was confirmed in isogenic PARK2 null lines. The mitochondrial phenotype was also seen in non-midbrain neurons differentiated from the PARK2 null line, as was the functional phenotype of reduced proliferation in culture. Whole genome expression profiling at various stages of differentiation confirmed the mitochondrial phenotype and identified pathways altered by PARK2 dysfunction that include PD-related genes. Our results are consistent with current model of PARK2 function where damaged mitochondria are targeted for degradation via a PARK2/PINK1-mediated mechanism.
在这项研究中，我们使用患者特异性和同源 PARK2 诱导的多能干细胞（iPSC）来表明 PARK2 突变会改变神经元的增殖。与年龄匹配的对照相比，携带各种 PARK2 突变的帕金森病（PD）患者来源神经元中 TH（+）神经元的比例降低。这种减少伴随着线粒体：细胞体积分数（线粒体体积分数）的改变。在同源 PARK2 缺失系中也证实了相同的表型。PARK2 缺失系分化的非中脑神经元也出现了线粒体表型，以及培养中增殖减少的功能表型。在分化的不同阶段进行全基因组表达谱分析证实了线粒体表型，并确定了 PARK2 功能障碍改变的途径，包括与 PD 相关的基因。我们的结果与当前的 PARK2 功能模型一致，其中受损的线粒体通过 PARK2/PINK1 介导的机制被靶向降解。
