DJ-1-binding compounds prevent oxidative stress-induced cell death and movement defect in Parkinson's disease model rats.
Parkinson's disease (PD) is caused by neuronal cell death. Although a precursor of dopamine and inhibitors of dopamine degradation have been used for PD therapy, cell death progresses during treatment. DJ-1, a causative gene product of a familial form of PD, PARK7, plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to result in the onset of PD. Superfluous oxidation of cysteine at amino acid 106 (C106) of DJ-1 renders DJ-1 inactive, and such oxidized DJ-1 has been observed in patients with the sporadic form of PD. In this study, we isolated compounds that bind to the region at C106 by a virtual screening. These compounds prevented oxidative stress-induced death of SH-SY5Y cells, embryonic stem cell-derived dopaminergic cells and primary neuronal cells of the ventral mesencephalon, but not that of DJ-1-knockdown cells of SH-SY5Y and NIH3T3 cells, indicating that the effect of the compounds is specific to DJ-1. These compounds inhibited production of reactive oxygen species and restored activities of mitochondrial complex I and tyrosine hydroxylase that had been compromised by oxidative stress. These compounds prevented dopaminergic cell death in the substantia nigra and restored movement abnormality in 6-hydroxyldopamine-injected PD model rats. One mechanism of action of these compounds is prevention of superfluous oxidation of DJ-1, and the compounds passed through the blood-brain barrier in vitro. Taken together, the results indicate that these compounds should become fundamental drugs for PD therapy.
Miyazaki
Shin
S
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yanagida
Takashi
T
Nunome
Kana
K
Ishikawa
Shizuma
S
Inden
Masatoshi
M
Kitamura
Yoshihisa
Y
Nakagawa
Shinsuke
S
Taira
Takahiro
T
Hirota
Kosaku
K
Niwa
Masami
M
Iguchi-Ariga
Sanae M M
SM
Ariga
Hiroyoshi
H
D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009069:Movement Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D000071617:Protein Deglycase DJ-1; D017434:Protein Structure, Tertiary; D051381:Rats
D000978:Antiparkinson Agents; D008869:Microtubule-Associated Proteins; C404267:PARK7 protein, rat; D000071617:Protein Deglycase DJ-1