title: Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant.
abstract: The I93M mutation in ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) was reported in one German family with autosomal dominant Parkinson's disease (PD). The causative role of the mutation has, however, been questioned. We generated transgenic (Tg) mice carrying human UCHL1 under control of the PDGF-B promoter; two independent lines were generated with the I93M mutation (a high- and low-expressing line) and one line with wild-type human UCH-L1. We found a significant reduction in the dopaminergic neurons in the substantia nigra and the dopamine content in the striatum in the high-expressing I93M Tg mice as compared with non-Tg mice at 20 weeks of age. Although these changes were absent in the low-expressing I93M Tg mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment profoundly reduced dopaminergic neurons in this line as compared with wild-type Tg or non-Tg mice. Abnormal neuropathologies were also observed, such as silver staining-positive argyrophilic grains in the perikarya of degenerating dopaminergic neurons, in I93M Tg mice. The midbrains of I93M Tg mice contained increased amounts of insoluble UCH-L1 as compared with those of non-Tg mice, perhaps resulting in a toxic gain of function. Collectively, our data represent in vivo evidence that expression of UCHL1(I93M) leads to the degeneration of dopaminergic neurons.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatory, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Setsuie
authors.forename: Yu-Lai
authors.initials: YL
authors.lastname: Wang
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Nobutsune
authors.initials: N
authors.lastname: Ichihara
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.forename: Akiko
authors.initials: A
authors.lastname: Furuta
authors.forename: Yae
authors.initials: Y
authors.lastname: Sano
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Sun
authors.forename: Jungkee
authors.initials: J
authors.lastname: Kwon
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kabuta
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshimi
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Aoki
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Mami
authors.initials: M
authors.lastname: Noda
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D004298:Dopamine