Effects of UCH-L1 on α-synuclein over-expression mouse model of Parkinson’s disease
| العنوان: | Effects of UCH-L1 on α-synuclein over-expression mouse model of Parkinson’s disease |
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| المؤلفون: | Keiji Wada, Tomohiro Kabuta, Tomoko Nihira, Hideki Mochizuki, Keiichiro Wada, Rieko Setsuie, Toru Yasuda, Xu-Qing Cao, Nobutaka Hattori, Yong-Ri Ren, Yoshikuni Mizuno |
| المصدر: | Journal of Neurochemistry. 108:932-944 |
| بيانات النشر: | Wiley, 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Parkinson's disease, Dopamine, Mutant, Mice, Transgenic, Biology, medicine.disease_cause, Biochemistry, Gene product, Mice, Cellular and Molecular Neuroscience, Internal medicine, medicine, Animals, Humans, Missense mutation, Genetic Predisposition to Disease, Aged, Brain Chemistry, Mice, Knockout, Neurons, Mutation, Cell Death, Dopaminergic, Dystrophy, Parkinson Disease, medicine.disease, Ubiquitin carboxy-terminal hydrolase L1, Mice, Inbred C57BL, Substantia Nigra, Disease Models, Animal, Endocrinology, Nerve Degeneration, alpha-Synuclein, Female, Ubiquitin Thiolesterase |
| الوصف: | 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 (alphaSyn). Immunohistochemistry of midbrain sections of a patient with sporadic PD showed alphaSyn- 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 alphaSyn 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 alphaSyn-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. |
| تدمد: | 1471-4159 0022-3042 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6a51676f0c2b2a818de42c7323390b6 https://doi.org/10.1111/j.1471-4159.2008.05827.x |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e6a51676f0c2b2a818de42c7323390b6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14714159 00223042 |
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