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PMID:23792957

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Citation

Björkblom, B, Adilbayeva, A, Maple-Grødem, J, Piston, D, Ökvist, M, Xu, XM, Brede, C, Larsen, JP and Møller, SG (2013) Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity. J. Biol. Chem. 288:22809-20

Abstract

The progressive loss of motor control due to reduction of dopamine-producing neurons in the substantia nigra pars compacta and decreased striatal dopamine levels are the classically described features of Parkinson disease (PD). Neuronal damage also progresses to other regions of the brain, and additional non-motor dysfunctions are common. Accumulation of environmental toxins, such as pesticides and metals, are suggested risk factors for the development of typical late onset PD, although genetic factors seem to be substantial in early onset cases. Mutations of DJ-1 are known to cause a form of recessive early onset Parkinson disease, highlighting an important functional role for DJ-1 in early disease prevention. This study identifies human DJ-1 as a metal-binding protein able to evidently bind copper as well as toxic mercury ions in vitro. The study further characterizes the cytoprotective function of DJ-1 and PD-mutated variants of DJ-1 with respect to induced metal cytotoxicity. The results show that expression of DJ-1 enhances the cells' protective mechanisms against induced metal toxicity and that this protection is lost for DJ-1 PD mutations A104T and D149A. The study also shows that oxidation site-mutated DJ-1 C106A retains its ability to protect cells. We also show that concomitant addition of dopamine exposure sensitizes cells to metal-induced cytotoxicity. We also confirm that redox-active dopamine adducts enhance metal-catalyzed oxidation of intracellular proteins in vivo by use of live cell imaging of redox-sensitive S3roGFP. The study indicates that even a small genetic alteration can sensitize cells to metal-induced cell death, a finding that may revive the interest in exogenous factors in the etiology of PD.

Links

PubMed PMC3829365 Online version:10.1074/jbc.M113.482091

Keywords

Animals; Base Sequence; Cell Line; Copper/toxicity; DNA Primers; Dopamine/pharmacology; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins/chemistry; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Mercury/toxicity; Mice; Models, Molecular; Oncogene Proteins/chemistry; Oncogene Proteins/genetics; Oncogene Proteins/metabolism; Oxidation-Reduction; Parkinson Disease/metabolism; Protein Binding

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PARK7

enables

GO:0005507: copper ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0010273: detoxification of copper ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0050787: detoxification of mercury ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PARK7

enables

GO:0045340: mercury ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PARK7

involved_in

GO:0010273: detoxification of copper ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PARK7

involved_in

GO:0050787: detoxification of mercury ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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