Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases
Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases
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DOI：
10.1074/jbc.m314124200
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发表时间：
2004-03-26
影响因子：
4.8
通讯作者：
Li, L
中科院分区：
文献类型：
--
作者：
Choi, J;Levey, AI;Li, L
阿尔茨海默病（AD）和帕金森病（PD）是两种最常见的神经退行性疾病，它们要么以相对罕见的家族性形式出现，要么以常见的散发性形式出现。几种单基因家族性AD和PD形式的潜在遗传缺陷最近已被确定，然而，其他AD和PD病例，特别是散发性病例的病因仍不清楚。为了深入了解AD和PD所涉及的致病机制，我们使用蛋白质组学方法来鉴定在特发性AD和PD大脑中表达水平改变和/或发生氧化修饰的蛋白质。在此，我们报告泛素羧基末端水解酶L1（UCH - L1）的蛋白质水平在特发性PD以及AD大脑中下调，UCH - L1是一种神经元去泛素化酶，其突变与早发性家族性PD有关。通过结合二维凝胶电泳和质谱分析，我们鉴定出了三个人脑UCH - L1异构体，一种全长形式和两种氨基末端截短形式。我们的蛋白质组学分析显示，全长UCH - L1是AD和PD大脑中氧化损伤的主要靶点，它被羰基形成、甲硫氨酸氧化和半胱氨酸氧化广泛修饰。此外，免疫组织化学研究表明，明显的UCH - L1免疫染色与神经原纤维缠结有关，并且可溶性UCH - L1蛋白水平与AD大脑中缠结的数量成反比。总之，这些结果提供了证据，支持神经元泛素化/去泛素化机制的氧化损伤与散发性AD和PD的发病机制之间存在直接联系。
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases that occur either in relatively rare, familial forms or in common, sporadic forms. The genetic defects underlying several monogenic familial forms of AD and PD have recently been identified, however, the causes of other AD and PD cases, particularly sporadic cases, remain unclear. To gain insights into the pathogenic mechanisms involved in AD and PD, we used a proteomic approach to identify proteins with altered expression levels and/or oxidative modifications in idiopathic AD and PD brains. Here, we report that the protein level of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), a neuronal de-ubiquitinating enzyme whose mutation has been linked to an early-onset familial PD, is down-regulated in idiopathic PD as well as AD brains. By using a combination of two-dimensional gel electrophoresis and mass spectrometry, we have identified three human brain UCH-L1 isoforms, a full-length form and two amino-terminally truncated forms. Our proteomic analyses reveal that the full-length UCH-L1 is a major target of oxidative damage in AD and PD brains, which is extensively modified by carbonyl formation, methionine oxidation, and cysteine oxidation. Furthermore, immunohistochemical studies show that prominent UCH-L1 immunostaining is associated with neurofibrillary tangles and that the level of soluble UCH-L1 protein is inversely proportional to the number of tangles in AD brains. Together, these results provide evidence supporting a direct link between oxidative damage to the neuronal ubiquitination/de-ubiquitination machinery and the pathogenesis of sporadic AD and PD.