Effects of UCH-L1 on alpha-synuclein over-expression mouse model of Parkinson's disease.
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.
Yasuda
Toru
T
Research Institute for Diseases of Old Age, Juntendo University, Tokyo, Japan.
Nihira
Tomoko
T
Ren
Yong-Ri
YR
Cao
Xu-Qing
XQ
Wada
Keiichiro
K
Setsuie
Rieko
R
Kabuta
Tomohiro
T
Wada
Keiji
K
Hattori
Nobutaka
N
Mizuno
Yoshikuni
Y
Mochizuki
Hideki
H
D000368:Aged; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
C482860:UCHL1 protein, human; D051844:alpha-Synuclein; D043222:Ubiquitin Thiolesterase; D004298:Dopamine