Effects of UCH-L1 on α-synuclein over-expression mouse model of Parkinson's disease |
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Authors: | Toru Yasuda Tomoko Nihira Yong-Ri Ren Xu-Qing Cao† Keiichiro Wada† Rieko Setsuie‡ Tomohiro Kabuta‡ Keiji Wada‡ Nobutaka Hattori† Yoshikuni Mizuno Hideki Mochizuki† |
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Institution: | Research Institute for Diseases of Old Age, Juntendo University, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan |
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Abstract: | 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-L1Ile93Met). 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 α-synuclein (αSyn). Immunohistochemistry of midbrain sections of a patient with sporadic PD showed αSyn- 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 αSyn for 4 weeks significantly enhanced the loss of nigral DA cell bodies in UCH-L1Ile93Met-Tg mice, but had weak effects in age-matched UCH-L1wild-type-Tg mice and non-Tg littermates. In contrast, the extent of αSyn-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-L1Ile93Met 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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Keywords: | α-synuclein adeno-associated virus dopaminergic neurons Parkinson's disease ubiquitin carboxy-terminal hydrolase-L1 |
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