Cookson Mark R
Laboratory of Neurogenetics National Institute on Agins, NIH, Bethesda, MD 20892, USA.
Neuromolecular Med. 2003;3(1):1-13. doi: 10.1385/NMM:3:1:1.
Mutations in the Parkin gene are associated with Parkinson s disease (PD). The gene product has been shown to be an E3 protein-ubiquitin ligase, catalyzing the addition of ubiquitin to target proteins prior to their destruction via the proteasome. This activity is thus key in regulating the turnover of substrate proteins. A predictive hypothesis for how this results in PD is that the misregulation of proteasomal degradation of Parkin s substrates is deleterious to neurons. Several different laboratories have identified alternate candidate proteins. In this review, the likelihood of each of the proposed substrates for parkin being robust will be evaluated. The distribution and abundance of the proteins will be examined for clues as to which are the pathologically important substrates for parkin. The possibility that loss of regulation of turnover of one or more of these substrates contributes to the selective neurodegeneration seen in PD is also discussed.
帕金森病（PD）与帕金基因的突变有关。该基因产物已被证明是一种E3蛋白泛素连接酶，在靶蛋白通过蛋白酶体被破坏之前催化泛素添加到靶蛋白上。因此，这种活性是调节底物蛋白周转的关键。关于这如何导致帕金森病的一个预测性假说是，帕金底物的蛋白酶体降解失调对神经元有害。几个不同的实验室已经鉴定出替代候选蛋白。在这篇综述中，将评估每种提出的帕金底物的可能性是否可靠。将检查这些蛋白质的分布和丰度，以寻找关于哪些是帕金在病理上重要的底物的线索。还讨论了这些底物中一种或多种周转调节丧失导致帕金森病中所见选择性神经变性的可能性。
