Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Hum Mol Genet. 2012 Jun 1;21(11):2514-23. doi: 10.1093/hmg/dds070. Epub 2012 Mar 2.
Neddylation is a posttranslational modification that plays important roles in regulating protein structure and function by covalently conjugating NEDD8, an ubiquitin-like small molecule, to the substrate. Here, we report that Parkinson's disease (PD)-related parkin and PINK1 are NEDD8 conjugated. Neddylation of parkin and PINK1 results in increased E3 ligase activity of parkin and selective stabilization of the 55 kDa PINK1 fragment. Expression of dAPP-BP1, a NEDD8 activation enzyme subunit, in Drosophila suppresses abnormalities induced by dPINK1 RNAi. PD neurotoxin MPP(+) inhibits neddylation of both parkin and PINK1. NEDD8 immunoreactivity is associated with Lewy bodies in midbrain dopaminergic neurons of PD patients. Together, these results suggest that parkin and PINK1 are regulated by neddylation and that impaired NEDD8 modification of these proteins likely contributes to PD pathogenesis.
类泛素化是一种翻译后修饰，通过将 NEDD8（一种泛素样小分子）共价连接到底物上来调节蛋白质结构和功能，发挥重要作用。在这里，我们报告帕金森病（PD）相关的 parkin 和 PINK1 是 NEDD8 缀合的。parkin 和 PINK1 的类泛素化导致 parkin 的 E3 连接酶活性增加，并且选择性稳定 55 kDa 的 PINK1 片段。果蝇中 dAPP-BP1（一种 NEDD8 激活酶亚基）的表达可抑制 dPINK1 RNAi 诱导的异常。PD 神经毒素 MPP(+)抑制 parkin 和 PINK1 的类泛素化。NEDD8 免疫反应性与 PD 患者中脑多巴胺能神经元中的路易体有关。总之，这些结果表明 parkin 和 PINK1 受类泛素化调节，这些蛋白的 NEDD8 修饰受损可能导致 PD 的发病机制。
