biostudies-literatureUnknown8(4)Aron LThe 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 DJPLoS biologye1000349https://www.ebi.ac.uk/biostudies/studies/S-EPMC2850379biostudies-literaturePro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.PMC2850379Klein RKlein PAron LWurst WPham TTKramer ERfalsePro-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 DJ2010-01-01T00:00:00Z2010 Apr2025-04-22T01:04:52.077Z2019-03-27T00:29:58ZS-EPMC28503792038672410.1371/journal.pbio.1000349