Pael receptor is involved in dopamine metabolism in the nigrostriatal system

• Published in: Neuroscience research 2007-12, Vol.59 (4), p.413-425
• Main Authors: Imai, Yuzuru, Inoue, Haruhisa, Kataoka, Ayane, Hua-Qin, Wang, Masuda, Masao, Ikeda, Toshio, Tsukita, Kayoko, Soda, Mariko, Kodama, Tohru, Fuwa, Tatsu, Honda, Yoshiko, Kaneko, Satoshi, Matsumoto, Sadayuki, Wakamatsu, Kazumasa, Ito, Shosuke, Miura, Masami, Aosaki, Toshihiko, Itohara, Shigeyoshi, Takahashi, Ryosuke
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; 3,4-Dihydroxyphenylacetic Acid - metabolism; 6-OHDA; Animals; AR-JP; Corpus Striatum - metabolism; Corpus Striatum - physiopathology; Dopamine - metabolism; Drug Resistance - genetics; Genetic Predisposition to Disease - genetics; GPR37; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; MPTP; Neural Pathways - metabolism; Neural Pathways - physiopathology; Neurotoxins - toxicity; Oxidopamine - toxicity; Parkin; Parkinson's disease; Parkinsonian Disorders - genetics; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - physiopathology; Receptors, G-Protein-Coupled - genetics; Striatum; Substantia nigra; Substantia Nigra - metabolism; Substantia Nigra - physiopathology; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2007.08.005

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.