title: Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.
abstract: 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.
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, Martinsried, Germany.
authors.forename: Liviu
authors.initials: L
authors.lastname: Aron
authors.forename: Pontus
authors.initials: P
authors.lastname: Klein
authors.forename: Thu-Trang
authors.initials: TT
authors.lastname: Pham
authors.forename: Edgar R
authors.initials: ER
authors.lastname: Kramer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D064026:Calbindins; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D054464:Peroxiredoxins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology / Q000502:physiology; D000071617:Protein Deglycase DJ-1; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D064026:Calbindins; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D015513:Oncogene Proteins; D064030:S100 Calcium Binding Protein G; D054464:Peroxiredoxins; D019869:Phosphatidylinositol 3-Kinases; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D018631:ras Proteins; D004298:Dopamine
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14807-12
references.pmid: 17766438
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13670-5
references.pmid: 16155123
references.citation: Eur J Neurosci. 2004 Feb;19(4):845-54
references.pmid: 15009131
references.citation: Dev Biol. 2000 May 15;221(2):404-18
references.pmid: 10790335
references.citation: Brain. 1991 Oct;114 ( Pt 5):2283-301
references.pmid: 1933245
references.citation: Hum Gene Ther. 2009 May;20(5):430-1
references.pmid: 19438403
references.citation: Neuron. 2001 Dec 6;32(5):801-14
references.pmid: 11738027
references.citation: Cell Death Differ. 2008 Sep;15(9):1510-21
references.pmid: 18497757
references.citation: FEBS Lett. 2008 Apr 2;582(7):1151-6
references.pmid: 18339323
references.citation: Cancer Cell. 2007 Jun;11(6):555-69
references.pmid: 17560336
references.citation: Trends Neurosci. 2007 May;30(5):244-50
references.pmid: 17418429
references.citation: Mech Dev. 1994 Feb;45(2):139-45
references.pmid: 8199050
references.citation: Oncogene. 2008 Sep 18;27(41):5443-53
references.pmid: 18794879
references.citation: FEBS Lett. 2005 Jul 4;579(17):3789-96
references.pmid: 15978587
references.citation: Nat Neurosci. 2001 Nov;4(11):1071-8
references.pmid: 11593232
references.citation: Curr Opin Neurobiol. 2008 Jun;18(3):297-306
references.pmid: 18678254
references.citation: Science. 2003 Jan 10;299(5604):256-9
references.pmid: 12446870
references.citation: Cell. 1994 Mar 11;76(5):875-88
references.pmid: 8124723
references.citation: Biochem Biophys Res Commun. 1997 Feb 13;231(2):509-13
references.pmid: 9070310
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5215-20
references.pmid: 15784737
references.citation: Brain Res. 2005 Apr 11;1041(1):102-11
references.pmid: 15804505
references.citation: J Neurosci Methods. 2005 Apr 15;143(1):27-32
references.pmid: 15763133
references.citation: Curr Biol. 2005 Sep 6;15(17):1578-82
references.pmid: 16139214
references.citation: PLoS Biol. 2007 Mar;5(3):e39
references.pmid: 17298183
references.citation: Curr Neurol Neurosci Rep. 2008 Jul;8(4):288-96
references.pmid: 18590612
references.citation: Annu Rev Biochem. 2005;74:29-52
references.pmid: 15952880
references.citation: Brain Res. 1990 Sep 3;526(2):303-7
references.pmid: 2257487
references.citation: Nat Neurosci. 2008 Jul;11(7):755-61
references.pmid: 18536709
references.citation: Behav Pharmacol. 2008 Sep;19(5-6):566-74
references.pmid: 18690111
references.citation: Neuron. 2005 Feb 17;45(4):489-96
references.pmid: 15721235
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18757-62
references.pmid: 17116866
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9691-6
references.pmid: 15983381
references.citation: Trends Neurosci. 2003 Apr;26(4):215-21
references.pmid: 12689773
references.citation: Cancer Cell. 2005 Mar;7(3):263-73
references.pmid: 15766664
references.citation: J Biol Chem. 2005 Jun 3;280(22):21418-26
references.pmid: 15799973
references.citation: Mol Cell Neurosci. 2007 Mar;34(3):400-8
references.pmid: 17208451
references.citation: EMBO J. 1996 Dec 2;15(23):6584-94
references.pmid: 8978685
references.citation: Hum Mol Genet. 2005 Jul 1;14(13):1709-25
references.pmid: 15888489
references.citation: Nat Rev Genet. 2009 Jun;10(6):359-70
references.pmid: 19434080
references.citation: EMBO Rep. 2004 Feb;5(2):213-8
references.pmid: 14749723
references.citation: Development. 2004 Mar;131(5):1145-55
references.pmid: 14973278
references.citation: Genes Brain Behav. 2010 Apr;9(3):305-17
references.pmid: 20039949
references.citation: Trends Neurosci. 2007 Apr;30(4):159-66
references.pmid: 17339056
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1111-6
references.pmid: 19144925
references.citation: J Cell Biol. 2000 Dec 25;151(7):1537-48
references.pmid: 11134081
references.citation: Dev Biol. 1998 Dec 15;204(2):432-50
references.pmid: 9882481
references.citation: Genetics. 2005 Nov;171(3):1057-81
references.pmid: 15965261
references.citation: Neuron. 2006 Apr 6;50(1):35-47
references.pmid: 16600854
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20049-54
references.pmid: 18056810
references.citation: J Neurochem. 2009 Jul;110(1):23-33
references.pmid: 19490361
references.citation: Mol Neurodegener. 2007 May 29;2:10
references.pmid: 17535435
references.citation: Biochem Biophys Res Commun. 2009 Jun 12;383(4):469-74
references.pmid: 19371728
references.citation: Ann Neurol. 2008 Dec;64 Suppl 2:S3-15
references.pmid: 19127586
references.citation: Neuron. 2003 Sep 11;39(6):889-909
references.pmid: 12971891
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10244-9
references.pmid: 18626009
references.citation: Nature. 2007 Jul 5;448(7149):73-7
references.pmid: 17611540
references.citation: Nat Neurosci. 2008 Jul;11(7):735-6
references.pmid: 18575468
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12517-22
references.pmid: 16894167
references.citation: FEBS Lett. 2006 May 29;580(13):3121-8
references.pmid: 16684527
references.citation: Neurodegeneration. 1996 Dec;5(4):313-8
references.pmid: 9117542
references.citation: Curr Biol. 2005 Sep 6;15(17):1572-7
references.pmid: 16139213
references.citation: Neuroscience. 1996 Nov;75(2):523-33
references.pmid: 8931015
references.citation: J Comp Neurol. 2007 Jan 20;500(3):585-99
references.pmid: 17120294
references.citation: Neuron. 2009 Apr 30;62(2):218-29
references.pmid: 19409267