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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Parkinson's disease-associated mutations in alpha-synuclein and UCH-L1 inhibit the unconventional secretion of UCH-L1.
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Parkinson's disease-associated mutations in alpha-synuclein and UCH-L1 inhibit the unconventional secretion of UCH-L1.

机译：帕金森病与α-突触核蛋白和UCH-L1的疾病相关的突变抑制了UCH-L1的非常规分泌。

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摘要

Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is an intracellular protein abundantly expressed in neurons, and a mutation in UCH-L1 has been identified in familial Parkinson's disease. UCH-L1 has been detected in human cerebrospinal fluid, raising the possibility that UCH-L1 is secreted from neurons. In the present study, we showed that a portion of UCH-L1 is secreted from cultured cells. The secretion of D30K UCH-L1, which lacks ubiquitin binding activity, was decreased compared with that of wild-type UCH-L1, while the secretion of C90S UCH-L1, which lacks hydrolase activity, was not. Treatment with Brefeldin A, an inhibitor of vesicle transport from the endoplasmic reticulum to the Golgi, did not block the secretion of UCH-L1, indicating that UCH-L1 is secreted by an unconventional pathway. The UCH-L1 sequence from Leu-32 to Leu-39 is similar to the unconventional secretory signal sequence of engrailed 2, and substitution of the leucines within this region (L32S/L32A/L34S/L34A/L39S/L39A) reduced the secretion of UCH-L1. We found that the Parkinson's disease-associated mutation I93M in UCH-L1 decreased the secretion of I93M UCH-L1. In addition, Parkinson's disease-linked alpha-synuclein mutants reduced the secretion of endogenous UCH-L1. Our results indicate that the hydrolase activity is not necessary for the unconventional secretion of UCH-L1, and suggest that the ubiquitin binding activity and the sequence between Leu-32 and Leu-39 are involved in the secretion. Moreover, the secretion of UCH-L1 could be involved in the pathology of Parkinson's disease.
机译：泛素羧基末端水解酶L1（UCH-L1）是在神经元中大量表达的细胞内蛋白，在家族性帕金森氏病中已确定UCH-L1发生突变。在人脑脊髓液中已检测到UCH-L1，从而增加了从神经元分泌UCH-L1的可能性。在本研究中，我们显示了UCH-L1的一部分是从培养细胞中分泌的。与野生型UCH-L1相比，缺乏泛素结合活性的D30K UCH-L1的分泌减少，而没有水解酶活性的C90S UCH-L1的分泌却没有。布雷菲德菌素A（一种从内质网到高尔基体的小泡转运抑制剂）的治疗没有阻止UCH-L1的分泌，表明UCH-L1是通过非常规途径分泌的。从Leu-32到Leu-39的UCH-L1序列类似于陷入的2的非常规分泌信号序列，该区域内亮氨酸的取代（L32S / L32A / L34S / L34A / L39S / L39A）减少了UCH-L1。我们发现UCH-L1中与帕金森氏病相关的突变I93M减少了I93M UCH-L1的分泌。此外，帕金森氏病相关的α-突触核蛋白突变体减少了内源性UCH-L1的分泌。我们的结果表明，水解酶活性对于UCH-L1的非常规分泌不是必需的，并且表明泛素结合活性以及Leu-32和Leu-39之间的序列参与了分泌。而且，UCH-L1的分泌可能与帕金森氏病的病理有关。

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