DJ-1 protects against dopamine toxicity.
Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons. Dopamine is a highly toxic compound leading to generation of reactive oxygen species (ROS). DJ-1 mutations lead to early-onset inherited PD. Here, we show that DJ-1 protects against dopamine toxicity. Dopamine-exposure led to upregulation of DJ-1. Overexpression of DJ-1 increased cell resistance to dopamine toxicity and reduced intracellular ROS. Contrary effects were achieved when DJ-1 levels were reduced by siRNA. Similarly, in vivo striatal administration of 6-hydroxydopamine led to upregulation of DJ-1. Upregulation of DJ-1 was mediated by the MAP kinases pathway through activation of ERK 1, 2 in vitro and in vivo. Hence, oxidative stress, generated by free cytoplasmic dopamine, leads to upregulation of DJ-1 through the MAP kinases pathway. This mechanism elucidates how mutations in DJ-1 prompt PD and imply that modulation of DJ-1 may serve as a novel neuroprotective modality.
Lev
Nirit
N
Department of Neurology, Felsenstein Medical Research Centre, Rabin Medical Centre, Tel Aviv University, Petah-Tikva, Israel. lev.nirit@gmail.com
Ickowicz
Debby
D
Barhum
Yael
Y
Lev
Shaul
S
Melamed
Eldad
E
Offen
Daniel
D
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D004298:Dopamine