期刊
NEUROCHEMISTRY INTERNATIONAL
卷 59, 期 2, 页码 251-258出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2011.05.012
关键词
UCH-L1; Parkinson's disease; Unconventional secretion; alpha-Synuclein
资金
- Ministry of Health, Labour and Welfare of Japan
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Ministry of Health, Labour and Welfare, Japan
- National Institute of Biomedical Innovation (NIBIO), Japan
- Grants-in-Aid for Scientific Research [22790838, 22020038, 22560454, 23650199, 22659172, 23390237] Funding Source: KAKEN
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. (C) 2011 Elsevier B.V. All rights reserved.
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