The effects of oxidative stress on parkin and other E3 ligases
The effects of oxidative stress on parkin and other E3 ligases
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DOI：
10.1111/j.1471-4159.2007.04911.x
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发表时间：
2007-12-01
影响因子：
4.7
通讯作者：
Schlossmacher, Michael G.
中科院分区：
文献类型：
--
作者：
LaVoie, Matthew J.;Cortese, Giuseppe P.;Schlossmacher, Michael G.
帕金森基因内的常染色体隐性突变与黑质和蓝斑变性以及遗传形式的帕金森病（PD）有关。由于帕金森氏病的功能丧失突变是帕金森氏病家族变异的原因，影响野生型帕金森氏病的条件可能与特发性疾病的风险增加有关。先前的研究揭示了parkin蛋白对多巴胺（DA）诱导的聚集和失活的独特脆弱性。在这项研究中，我们比较了几种与parkin具有相同结构元件或泛素化活性的蛋白质。我们报道了几种细胞系和初级神经元中的氧化应激诱导parkin聚集成高分子量物种，其中至少一部分是自相关的同源多聚体。虽然过量DA会优先影响parkin，但所测试的E3蛋白在氧化应激下变得更不溶性，并且它们的易感性程度不同（例如parkin > HHARI与CHIP > c-Cbl > E6AP一致）。这些氧化应激条件也与帕金E3连接酶活性降低有关。与最近对α -突触核蛋白加工的研究类似，巨噬和蛋白酶体都参与了parkin的降解，蛋白酶体在正常的parkin周转中起主导作用，而巨噬在聚集性parkin的降解中更为重要。这些数据进一步强调了parkin对da诱导修饰的选择性脆弱性，首次证明了内源性和外源性表达的parkin能够部分通过自结合和低聚物的形成转变为不溶状态。
Autosomal recessive mutations within the Parkin gene are associated with degeneration of the substantia nigra and locus coeruleus and an inherited form of Parkinson's disease (PD). As loss-of-function mutations in parkin are responsible for a familial variant of PD, conditions that affect wild-type parkin are likely to be associated with increased risk of idiopathic disease. Previous studies uncovered a unique vulnerability of the parkin protein to dopamine (DA)-induced aggregation and inactivation. In this study, we compared several proteins that share structural elements or ubiquitinating activity with parkin. We report that oxidative stress in several cell lines and primary neurons induces the aggregation of parkin into high molecular weight species, at least a portion of which are self-associated homo-multimers. While parkin was preferentially affected by excess DA, each of the E3 proteins tested were made more insoluble by oxidative stress, and they varied in degree of susceptibility (e.g. parkin > HHARI congruent to CHIP > c-Cbl > E6AP). These conditions of oxidative stress were also associated with decreased parkin E3 ligase activity. Similar to recently conducted studies on alpha-synuclein processing, both macroautophagy and the proteasome participate in parkin degradation, with the proteasome playing the predominant role for normal parkin turnover and macroautophagy being more important in the degradation of aggregated parkin. These data further highlight the selective vulnerability of parkin to DA-induced modifications, demonstrating for the first time the ability of both endogenous and ectopically expressed parkin to transition into an insoluble state in part through self-association and oligomer formation.