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Aron, L.* ; Klein, P.* ; Pham, T.T. ; Kramer, E.R.* ; Wurst, W. ; Klein, R.*

Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.

PLoS Biol. 8:e1000349 (2010)
Verlagsversion Volltext DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Tumor-suppressor PTEN; Oxidative stress; Drosophila DJ-1; Cell-death; DJ-1-deficient mice; Tyrosine kinase; In-vivo; Disease; Midbrain; Mouse
ISSN (print) / ISBN 1544-9173
e-ISSN 1545-7885
Zeitschrift PLoS Biology
Quellenangaben Band: 8, Heft: 4, Seiten: , Artikelnummer: e1000349 Supplement: ,
Verlag Public Library of Science (PLoS)
Verlagsort San Francisco
Begutachtungsstatus Peer reviewed