Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.
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Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons. / Aron, Liviu; Klein, Pontus; Pham, Thu-Trang; Kramer, Edgar; Wurst, Wolfgang; Klein, Rüdiger.
in: PLOS BIOL, Jahrgang 8, Nr. 4, 4, 2010, S. 1000349.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.
AU - Aron, Liviu
AU - Klein, Pontus
AU - Pham, Thu-Trang
AU - Kramer, Edgar
AU - Wurst, Wolfgang
AU - Klein, Rüdiger
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Signal Transduction physiology
KW - histology
KW - Behavior, Animal physiology
KW - Cell Line
KW - Calcium-Binding Protein, Vitamin D-Dependent metabolism
KW - Cell Survival genetics
KW - Corpus Striatum anatomy
KW - Dopamine metabolism
KW - Drosophila melanogaster anatomy
KW - G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism
KW - Neurons pathology
KW - Oncogene Proteins genetics
KW - Parkinson Disease genetics
KW - Phosphatidylinositol 3-Kinases metabolism
KW - Photoreceptor Cells, Invertebrate cytology
KW - Proto-Oncogene Proteins c-ret genetics
KW - Substantia Nigra cytology
KW - ras Proteins genetics
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Signal Transduction physiology
KW - histology
KW - Behavior, Animal physiology
KW - Cell Line
KW - Calcium-Binding Protein, Vitamin D-Dependent metabolism
KW - Cell Survival genetics
KW - Corpus Striatum anatomy
KW - Dopamine metabolism
KW - Drosophila melanogaster anatomy
KW - G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism
KW - Neurons pathology
KW - Oncogene Proteins genetics
KW - Parkinson Disease genetics
KW - Phosphatidylinositol 3-Kinases metabolism
KW - Photoreceptor Cells, Invertebrate cytology
KW - Proto-Oncogene Proteins c-ret genetics
KW - Substantia Nigra cytology
KW - ras Proteins genetics
U2 - 10.1371/journal.pbio.1000349
DO - 10.1371/journal.pbio.1000349
M3 - SCORING: Zeitschriftenaufsatz
VL - 8
SP - 1000349
JO - PLOS BIOL
JF - PLOS BIOL
SN - 1544-9173
IS - 4
M1 - 4
ER -
