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. © 2010 aron et al.