Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.
The mechanisms underlying the selective death of substantia nigra (SN) neurons in Parkinson disease (PD) remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA) neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 and Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD.
Aron
Liviu
L
Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, Martinsried, Germany.
Klein
Pontus
P
Pham
Thu-Trang
TT
Kramer
Edgar R
ER
Wurst
Wolfgang
W
Klein
Rüdiger
R
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D064026:Calbindins; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D054464:Peroxiredoxins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology / Q000502:physiology; D000071617:Protein Deglycase DJ-1; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D064026:Calbindins; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D015513:Oncogene Proteins; D064030:S100 Calcium Binding Protein G; D054464:Peroxiredoxins; D019869:Phosphatidylinositol 3-Kinases; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D018631:ras Proteins; D004298:Dopamine
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