The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility
The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility
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DOI：
10.1016/s0092-8674(02)01012-7
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发表时间：
2002-10-18
期刊：
影响因子：
64.5
通讯作者：
Lansbury, PT
中科院分区：
文献类型：
--
作者：
Liu, YC;Fallon, L;Lansbury, PT
假设每种酶在体内表达单一的酶活性受到神经元酶泛素C-末端水解酶-L1（UCH-L1）与帕金森病（PD）的联系的挑战。UCH-L1，特别是那些与PD易感性较高相关的变异体，会导致α-突触核蛋白在培养细胞中的积累，这种作用不能用其公认的水解酶活性来解释。UCH-L1在此显示出第二种二聚化依赖性泛素连接酶活性。与PD风险降低相关的UCH-L1多态性变体（S18 Y）具有降低的连接酶活性，但与野生型酶相当的水解酶活性。因此，UCH-L1的连接酶活性以及水解酶活性可能在蛋白酶体蛋白降解中发挥作用，这是神经元健康的关键过程。
The assumption that each enzyme expresses a single enzymatic activity in vivo is challenged by the linkage of the neuronal enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1) to Parkinson's disease (PD). UCH-L1, especially those variants linked to higher susceptibility to PD, causes the accumulation of alpha-synuclein in cultured cells, an effect that cannot be explained by its recognized hydrolase activity. UCH-L1 is shown here to exhibit a second, dimerization-dependent, ubiquityl ligase activity. A polymorphic variant of UCH-L1 that is associated with decreased PD risk (S18Y) has reduced ligase activity but comparable hydrolase activity as the wild-type enzyme. Thus, the ligase activity as well as the hydrolase activity of UCH-L1 may play a role in proteasomal protein degradation, a critical process for neuronal health.