RGD Reference Report - DJ-1-binding compounds prevent oxidative stress-induced cell death and movement defect in Parkinson's disease model rats. - Rat Genome Database

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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 
Citation: Miyazaki S, etal., J Neurochem. 2008 Jun 1;105(6):2418-34. doi: 10.1111/j.1471-4159.2008.05327.x.
RGD ID: 13463452
Pubmed: PMID:18373560   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1471-4159.2008.05327.x   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Parkinsonism treatmentISOPark7 (Rattus norvegicus)13463452; 13463452 RGD 
Parkinsonism treatmentIMP 13463452 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Park7  (Parkinsonism associated deglycase)

Genes (Mus musculus)
Park7  (Parkinson disease (autosomal recessive, early onset) 7)

Genes (Homo sapiens)
PARK7  (Parkinsonism associated deglycase)


Additional Information