期刊
JOURNAL OF NEUROCHEMISTRY
卷 108, 期 4, 页码 932-944出版社
WILEY
DOI: 10.1111/j.1471-4159.2008.05827.x
关键词
alpha-synuclein; adeno-associated virus; dopaminergic neurons; Parkinson's disease; ubiquitin carboxy-terminal hydrolase-L1
资金
- High Technology Research Center
- National Institute of Biomedical Innovation
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Scientific Research from the Ministry of Health, Labour and Welfare of Japan
The rare inherited form of Parkinson's disease (PD), PARK5, is caused by a missense mutation in ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) gene, resulting in Ile93Met substitution in its gene product (UCH-L1(Ile93Met)). PARK5 is inherited in an autosomal-dominant mode, but whether the Ile93Met mutation gives rise to a gain-of-toxic-function or loss-of-function of UCH-L1 protein remains controversial. Here, we investigated the selective vulnerabilities of dopaminergic (DA) neurons in UCH-L1-transgenic (Tg) and spontaneous UCH-L1-null gracile axonal dystrophy mice to an important PD-causing insult, abnormal accumulation of alpha-synuclein (alpha Syn). Immunohistochemistry of midbrain sections of a patient with sporadic PD showed alpha Syn- and UCH-L1-double-positive Lewy bodies in nigral DA neurons, suggesting physical and/or functional interaction between the two proteins in human PD brain. Recombinant adeno-associated viral vector-mediated over-expression of alpha Syn for 4 weeks significantly enhanced the loss of nigral DA cell bodies in UCH-L1(Ile93Met)-Tg mice, but had weak effects in age-matched UCH-L1(wild-type)-Tg mice and non-Tg littermates. In contrast, the extent of alpha Syn-induced DA cell loss in gracile axonal dystrophy mice was not significantly different from wild-type littermates at 13-weeks post-injection. Our results support the hypothesis that PARK5 is caused by a gain-of-toxic-function of UCH-L1(Ile93Met) mutant, and suggest that regulation of UCH-L1 in nigral DA cells could be a future target for treatment of PD.
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