Stevens Daniel A, Lee Yunjong, Kang Ho Chul, Lee Byoung Dae, Lee Yun-Il, Bower Aaron, Jiang Haisong, Kang Sung-Ung, Andrabi Shaida A, Dawson Valina L, Shin Joo-Ho, Dawson Ted M
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685;
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 446-746, South Korea;
Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11696-701. doi: 10.1073/pnas.1500624112. Epub 2015 Aug 31.
Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death.
帕金蛋白的突变会导致早发性常染色体隐性帕金森病（PD），并且帕金蛋白的失活被认为与散发性PD有关。在小鼠腹侧中脑成年期敲除帕金蛋白会导致多巴胺能神经元随年龄增长而丧失，这种丧失依赖于帕金蛋白相互作用底物（PARIS）、锌指蛋白746（ZNF746）的积累及其对PGC-1α的转录抑制。在这里，我们表明，在小鼠腹侧中脑成年期敲除帕金蛋白会导致线粒体大小、数量和蛋白质标志物减少，这与线粒体生物发生缺陷一致。通过短发夹RNA敲低PARIS可防止线粒体质量的这种减少。在小鼠腹侧中脑过表达PARIS会导致线粒体数量和蛋白质标志物减少以及线粒体呼吸中依赖PGC-1α的缺陷。综上所述，这些结果表明帕金蛋白缺失会损害线粒体生物发生，导致线粒体池功能下降和细胞死亡。
