在帕金森病的细胞培养模型中,PINK1缺陷会导致线粒体功能障碍、蛋白酶体缺陷和α-突触核蛋白聚集。

PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson's disease.

作者信息

Liu Wencheng, Vives-Bauza Cristofol, Acín-Peréz- Rebeca, Yamamoto Ai, Tan Yingcai, Li Yanping, Magrané Jordi, Stavarache Mihaela A, Shaffer Sebastian, Chang Simon, Kaplitt Michael G, Huang Xin-Yun, Beal M Flint, Manfredi Giovanni, Li Chenjian

机构信息

Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, New York, USA.

出版信息

PLoS One. 2009;4(2):e4597. doi: 10.1371/journal.pone.0004597. Epub 2009 Feb 26.

Abstract

Mutations in PTEN induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. Here, we report that PINK1 exists as a dimer in mitochondrial protein complexes that co-migrate with respiratory chain complexes in sucrose gradients. PARK6 related mutations do not affect this dimerization and its associated complexes. Using in vitro cell culture systems, we found that mutant PINK1 or PINK1 knock-down caused deficits in mitochondrial respiration and ATP synthesis. Furthermore, proteasome function is impaired with a loss of PINK1. Importantly, these deficits are accompanied by increased alpha-synclein aggregation. Our results indicate that it will be important to delineate the relationship between mitochondrial functional deficits, proteasome dysfunction and alpha-synclein aggregation.

摘要

磷酸酶与张力蛋白同源物(PTEN)诱导激酶1(PINK1)是一种线粒体丝氨酸/苏氨酸激酶,其突变会导致常染色体隐性帕金森病(PD),即PARK6型。在此,我们报告PINK1在线粒体蛋白复合物中以二聚体形式存在,在蔗糖梯度中与呼吸链复合物共同迁移。与PARK6相关的突变并不影响这种二聚化及其相关复合物。利用体外细胞培养系统,我们发现突变型PINK1或PINK1基因敲低会导致线粒体呼吸和ATP合成缺陷。此外,PINK1缺失会损害蛋白酶体功能。重要的是,这些缺陷伴随着α-突触核蛋白聚集增加。我们的结果表明,阐明线粒体功能缺陷、蛋白酶体功能障碍与α-突触核蛋白聚集之间的关系将具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ffc/2644779/1dea83276c39/pone.0004597.g001.jpg

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