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- Title
DJ-1-binding compounds prevent oxidative stress-induced cell death and movement defect in Parkinson’s disease model rats.
- Authors
Miyazaki, Shin; Yanagida, Takashi; Nunome, Kana; Ishikawa, Shizuma; Inden, Masatoshi; Kitamura, Yoshihisa; Nakagawa, Shinsuke; Taira, Takahiro; Hirota, Kosaku; Niwa, Masami; Iguchi-Ariga, Sanae M. M.; Ariga, Hiroyoshi
- Abstract
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.
- Subjects
BINDING energy; NEUROTRANSMITTERS; CATECHOLAMINES; PARKINSON'S disease; BRAIN diseases; AMINO acids; AMINO compounds
- Publication
Journal of Neurochemistry, 2008, Vol 105, Issue 6, p2418
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2008.05327.x