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          Institute: MPI für Neurobiologie     Collection: Molecular Neurobiology     Display Documents

ID: 476993.0, MPI für Neurobiologie / Molecular Neurobiology
Pro-Survival Role for Parkinson's Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons
Authors:Aron, L.; Klein, P.; Pham, T. T.; Kramer, E. R.; Wurst, W.; Klein, R.
Date of Publication (YYYY-MM-DD):2010-04
Title of Journal:PLoS Biology
Journal Abbrev.:PLoS. Biol.
Issue / Number:4
Start Page:[1]
End Page:[16]
Sequence Number of Article:e1000349
Review Status:Peer-review
Audience:Not Specified
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Affiliations:MPI für Neurobiologie/Molecular Neurobiology (Klein)
External Affiliations:[Pham, Thu-Trang; Wurst, Wolfgang] Tech Univ Munich, Helmholtz Ctr Munich, Natl Ctr Dementia Res, Neuherberg, Germany.; [Kramer, Edgar R.] Univ Hamburg, Ctr Mol Neurobiol, D-2000 Hamburg, Germany.
Identifiers:ISI:000278125500003 [ID No:1]
ISSN:1544-9173 [ID No:2]
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