Aberrant molecular properties shared by familial Parkinson's disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1
Aberrant molecular properties shared by familial Parkinson's disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1
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DOI：
10.1093/hmg/ddn037
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发表时间：
2008-05-15
影响因子：
3.5
通讯作者：
Wada, Keiji
中科院分区：
文献类型：
--
作者：
Kabuta, Tomohiro;Setsuie, Rieko;Wada, Keiji
帕金森病（PD）是一种以多巴胺能神经元缺失为特征的神经退行性疾病。泛素C-末端水解酶L1（UCH-L1）中的I93 M突变与家族性PD相关，我们先前已经证明I93 M UCH-L1转基因小鼠表现出多巴胺能细胞丢失。超过90%的神经退行性疾病（包括PD）是偶发性的。然而，散发性PD以及与I93 M UCH-L1相关的PD的分子机制在很大程度上是未知的。UCH-L1在脑中含量丰富（占总可溶性蛋白的1-5%），是与散发性PD相关的氧化/羰基损伤的主要靶点。同样，异常微管动力学和微管蛋白聚合与几种神经退行性疾病相关，包括与17号染色体相关的额颞叶痴呆和帕金森综合征。在这里，我们表明，家族性PD相关突变体UCH-L1和羰基修饰的UCH-L1显示出共同的异常特性：与野生型UCH-L1相比，它们表现出增加的不溶性和与多种蛋白质的相互作用，这是几种神经退行性疾病相关突变体的特征。圆二色性分析表明两种UCH-L1变体的结构变化相似。我们进一步报告，与UCH-L1相互作用的蛋白质之一是微管蛋白，并且突变体或羰基修饰的UCH-L1与微管蛋白的异常相互作用调节微管蛋白聚合。这些发现可能是家族性PD中突变型UCH-L1毒性功能获得的基础。我们的研究结果还表明，羰基修饰的UCH-L1和随后的异常相互作用的羰基修饰的UCH-L1与多种蛋白质，包括微管蛋白，构成了散发性PD的原因之一。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. The I93M mutation in ubiquitin C-terminal hydrolase L1 (UCH-L1) is associated with familial PD, and we have previously shown that the I93M UCH-L1-transgenic mice exhibit dopaminergic cell loss. Over 90% of neurodegenerative diseases, including PD, occur sporadically. However, the molecular mechanisms underlying sporadic PD as well as PD associated with I93M UCH-L1 are largely unknown. UCH-L1 is abundant (1-5% of total soluble protein) in the brain and is a major target of oxidative/carbonyl damage associated with sporadic PD. As well, abnormal microtubule dynamics and tubulin polymerization are associated with several neurodegenerative diseases including frontotemporal dementia and parkinsonism linked to chromosome 17. Here we show that familial PD-associated mutant UCH-L1 and carbonyl-modified UCH-L1 display shared aberrant properties: compared with wild-type UCH-L1, they exhibit increased insolubility and elevated interactions with multiple proteins, which are characteristics of several neurodegenerative diseases-linked mutants. Circular dichroism analyses suggest similar structural changes in both UCH-L1 variants. We further report that one of the proteins interacting with UCH-L1 is tubulin, and that aberrant interaction of mutant or carbonyl-modified UCH-L1 with tubulin modulates tubulin polymerization. These findings may underlie the toxic gain of function by mutant UCH-L1 in familial PD. Our results also suggest that the carbonyl modification of UCH-L1 and subsequent abnormal interactions of carbonyl-modified UCH-L1 with multiple proteins, including tubulin, constitute one of the causes of sporadic PD.