Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant.
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.
Setsuie
Rieko
R
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatory, Kodaira, Tokyo 187-8502, Japan.
Wang
Yu-Lai
YL
Mochizuki
Hideki
H
Osaka
Hitoshi
H
Hayakawa
Hideki
H
Ichihara
Nobutsune
N
Li
Hang
H
Furuta
Akiko
A
Sano
Yae
Y
Sun
Ying-Jie
YJ
Kwon
Jungkee
J
Kabuta
Tomohiro
T
Yoshimi
Kenji
K
Aoki
Shunsuke
S
Mizuno
Yoshikuni
Y
Noda
Mami
M
Wada
Keiji
K
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
D017931:DNA Primers; D004298:Dopamine