Parkinson Disease Protein DJ-1 Binds Metals and Protects against Metal-induced Cytotoxicity
| Autor: | Benny Björkblom, Mats Ökvist, Jan Petter Larsen, Altynai Adilbayeva, Jodi Maple-Grødem, Simon Geir Møller, Dominik Piston, Xiang Ming Xu, Cato Brede |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Programmed cell death genetic structures Dopamine Cell- och molekylärbiologi Protein Deglycase DJ-1 Substantia nigra Biology medicine.disease_cause Biochemistry Cell Line Mice medicine Animals Homeostasis Humans Cytotoxicity Molecular Biology DNA Primers Oncogene Proteins Base Sequence Pars compacta Intracellular Signaling Peptides and Proteins Biochemistry and Molecular Biology Parkinson Disease Molecular Bases of Disease Mercury Cell Biology musculoskeletal system eye diseases Cell biology Cell culture sense organs human activities Oxidation-Reduction Copper Biokemi och molekylärbiologi Cell and Molecular Biology Oxidative stress Protein Binding medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 288:22809-22820 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m113.482091 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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