Oxidative neurodegeneration is prevented by UCP0045037, an allosteric modulator for the reduced form of DJ-1, a wild-type of familial Parkinson's disease-linked PARK7.
Although a loss-of-function mutation has been identified in familial Parkinson's disease PARK7, the wild-type of DJ-1 is known to act as an oxidative stress sensor in neuronal cells. Recently, we identified UCP0045037 as a compound that bound to the reduced form of DJ-1 by in silico virtual screening. In this study, we determined the neuroprotective effects of UCP0045037 against focal cerebral ischemia-induced neurodegeneration in rats. Hydrogen peroxide-induced cell death was significantly inhibited by UCP0045037 in both rat mesencephalic dopaminergic neurons and human normal SH-SY5Y cells. In contrast, DJ-1-knockdown SH-SY5Y cells lost the protective activity of UCP0045037. These results suggest that UCP0045037 interacts with endogenous DJ-1 and produces a neuroprotective response.
Yamane
Koichiro
K
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Kitamura
Yoshihisa
Y
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Yanagida
Takashi
T
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Takata
Kazuyuki
K
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Yanagisawa
Daijiro
D
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Taniguchi
Takashi
T
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Taira
Takahiro
T
Department of Molecular Cell Biology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo 409-3898, Japan.
Ariga
Hiroyoshi
H
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D000071617:Protein Deglycase DJ-1; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats
D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; C000588572:UCP0045037; D006861:Hydrogen Peroxide; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D000241:Adenosine