Pael receptor is involved in dopamine metabolism in the nigrostriatal system.
Pael receptor (Pael-R) has been identified as one of the substrates of Parkin, a ubiquitin ligase responsible for autosomal recessive juvenile Parkinsonism (AR-JP). When Parkin is inactivated, unfolded Pael-R accumulates in the endoplasmic reticulum and results in neuronal death by unfolded protein stress, suggesting that Pael-R has an important role in the pathogenesis of AR-JP. Here we report the analyses on Pael-R-deficient (KO) and Pael-R-transgenic (Tg) mice. The striatal dopamine (DA) level of Pael-R KO mice was only 60% of that in normal mice, while in Pael-R Tg mice, striatal 3,4-dihydroxyphenylacetic acid (DOPAC) as well as vesicular DA content increased. Moreover, the nigrostriatal dopaminergic neurons of Pael-R Tg mice are more vulnerable to Parkinson's disease-related neurotoxins while those of Pael-R KO mice are less. These results strongly suggest that the Pael-R signal regulates the amount of DA in the dopaminergic neurons and that excessive Pael-R expression renders dopaminergic neurons susceptible to chronic DA toxicity.
Imai
Yuzuru
Y
Laboratory for Motor System Neurodegeneration, RIKEN Brain Science Institute (BSI), Saitama, Japan. yimai@idac.tohoku.ac.jp
Inoue
Haruhisa
H
Kataoka
Ayane
A
Hua-Qin
Wang
W
Masuda
Masao
M
Ikeda
Toshio
T
Tsukita
Kayoko
K
Soda
Mariko
M
Kodama
Tohru
T
Fuwa
Tatsu
T
Honda
Yoshiko
Y
Kaneko
Satoshi
S
Matsumoto
Sadayuki
S
Wakamatsu
Kazumasa
K
Ito
Shosuke
S
Miura
Masami
M
Aosaki
Toshihiko
T
Itohara
Shigeyoshi
S
Takahashi
Ryosuke
R
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C480827:GPR37 receptor, human; D009498:Neurotoxins; D043562:Receptors, G-Protein-Coupled; D015102:3,4-Dihydroxyphenylacetic Acid; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine