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.
Mesh Terms:
Animals, Behavior, Animal, Calcium-Binding Protein, Vitamin D-Dependent, Cell Line, Cell Survival, Corpus Striatum, Dopamine, Drosophila melanogaster, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Humans, Mice, Mice, Knockout, Neurons, Oncogene Proteins, Parkinson Disease, Phosphatidylinositol 3-Kinases, Photoreceptor Cells, Invertebrate, Proto-Oncogene Proteins c-ret, Signal Transduction, Substantia Nigra, ras Proteins
PLoS Biol.
Date: Apr. 14, 2010
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