Sriram Sathya R, Li Xiaojie, Ko Han Seok, Chung Kenny K K, Wong Esther, Lim Kah Leong, Dawson Valina L, Dawson Ted M
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hum Mol Genet. 2005 Sep 1;14(17):2571-86. doi: 10.1093/hmg/ddi292. Epub 2005 Jul 27.
Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism. The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.
帕金森蛋白（parkin）的突变主要与常染色体隐性少年帕金森病相关。帕金森蛋白相关帕金森病（PD）发病的潜在机制被认为是由于帕金森蛋白E3泛素连接酶活性丧失。研究了帕金森蛋白中一系列错义及无义点突变，这些突变贯穿整个基因，代表了与帕金森蛋白相关帕金森病相关的多种遗传模式，检测了它们的E3连接酶活性、定位以及结合、泛素化和影响两个底物（突触核蛋白-1和氨酰-tRNA合成酶复合物辅因子p38）降解的能力。帕金森蛋白突变体在细胞内定位、与底物的结合及酶活性方面存在差异，但它们最终在降解底物的能力上存在缺陷。这些结果表明，并非所有帕金森蛋白突变都会导致其E3连接酶活性丧失，但由于溶解性、聚集、酶活性或靶向蛋白至蛋白酶体进行降解方面的缺陷，它们似乎都表现为功能丧失突变体。
