title: Knocking out DJ-1 attenuates astrocytes neuroprotection against 6-hydroxydopamine toxicity.
abstract: Astrocytes are the most abundant glial cell type in the brain. Impairment in astrocyte functions can critically influence neuronal survival and leads to neurodegeneration. Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by motor dysfunction that results from progressive neuronal loss. Astrocytic dysfunction was demonstrated in human samples and in experimental models of PD. Mutations in DJ-1 (PARK7) leading to loss of functional protein cause familial PD and enhance sensitivity to oxidative insults. Recently, an increase in DJ-1's expression was found in reactive astrocytes in various neurodegenerative disorders. Here we show that lack of DJ-1 attenuates astrocytes' ability to support neuronal cells, thereby leading to accelerated neuronal damage. DJ-1 knockout mice demonstrated increased vulnerability in vivo to 6-hydroxydopamine (6-OHDA) hemiparkinsonian PD model. Astrocytes isolated from DJ-1 knockout mice showed an inferior ability to protect human neuroblastoma cells against 6-OHDA insult both by co-culture and through their conditioned media, as compared to wild-type astrocytes. DJ-1 knockout astrocytes showed blunted ability to increase the expression of cellular protective mechanisms against oxidative stress mediated via Nrf-2 and HO-1 in response to exposure to 6-OHDA. These experiments demonstrated that lack of DJ-1 impairs astrocyte-mediated neuroprotection.
authors.affiliation: The Neuroscience Laboratory, Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Petah-Tikva, Israel. Lev.nirit@gmail.com
authors.forename: Nirit
authors.initials: N
authors.lastname: Lev
authors.forename: Yael
authors.initials: Y
authors.lastname: Barhum
authors.forename: Tali
authors.initials: T
authors.lastname: Ben-Zur
authors.forename: Eldad
authors.initials: E
authors.lastname: Melamed
authors.forename: Israel
authors.initials: I
authors.lastname: Steiner
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics*; D018384:Oxidative Stress; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1
chemical_list: D017077:Culture Media, Conditioned; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015513:Oncogene Proteins; D016627:Oxidopamine; D054464:Peroxiredoxins; D051547:Heme Oxygenase-1; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1
references.citation: J Neurochem. 2011 May;117(3):375-87
references.pmid: 21219333
references.citation: J Neural Transm (Vienna). 2009 Feb;116(2):151-60
references.pmid: 18974921
references.citation: Neurosci Lett. 2007 Sep 20;425(1):18-22
references.pmid: 17720313
references.citation: Oxid Med Cell Longev. 2009 Jan-Mar;2(1):36-42
references.pmid: 20046643
references.citation: Prog Neurobiol. 2004 Feb;72(2):111-27
references.pmid: 15063528
references.citation: Mol Neurodegener. 2009 Feb 25;4:12
references.pmid: 19243613
references.citation: Cell Tissue Res. 2005 Dec;322(3):503-7
references.pmid: 16047164
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18748-53
references.pmid: 18003894
references.citation: J Gerontol A Biol Sci Med Sci. 2013 Mar;68(3):215-25
references.pmid: 22887838
references.citation: Neuroscience. 2011 Nov 24;196:251-64
references.pmid: 21907265
references.citation: Science. 2003 Jan 10;299(5604):256-9
references.pmid: 12446870
references.citation: Neurobiol Dis. 2006 Oct;24(1):144-58
references.pmid: 16860563
references.citation: Curr Opin Neurol. 2001 Aug;14(4):483-9
references.pmid: 11470965
references.citation: Biochem Biophys Res Commun. 2006 Jul 7;345(3):967-72
references.pmid: 16707095
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3186-91
references.pmid: 20133695
references.citation: Neurosci Lett. 2010 Oct 15;483(3):201-5
references.pmid: 20708070
references.citation: Brain Res. 2005 Apr 11;1041(1):102-11
references.pmid: 15804505
references.citation: Neuropathology. 2009 Apr;29(2):125-31
references.pmid: 18647263
references.citation: Mov Disord. 2011 Jan;26(1):6-17
references.pmid: 21322014
references.citation: J Biol Chem. 2008 Feb 15;283(7):4022-30
references.pmid: 18042550
references.citation: Neurobiol Dis. 2009 Jan;33(1):28-36
references.pmid: 18930142
references.citation: Hum Mol Genet. 2012 Jul 1;21(13):3013-24
references.pmid: 22492997
references.citation: Brain. 2010 Mar;133(Pt 3):713-26
references.pmid: 20157014
references.citation: J Biol Chem. 2007 May 4;282(18):13680-91
references.pmid: 17331951
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9691-6
references.pmid: 15983381
references.citation: Ann Neurol. 2011 Mar;69(3):570-80
references.pmid: 21400565
references.citation: Mov Disord. 2008 Mar 15;23(4):474-83
references.pmid: 18044695
references.citation: Neurochem Res. 2011 Aug;36(8):1452-63
references.pmid: 21484266
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9103-8
references.pmid: 15181200
references.citation: J Mol Neurosci. 2012 Sep;48(1):176-84
references.pmid: 22638856
references.citation: Cytotherapy. 2012 Jan;14(1):45-55
references.pmid: 22040110
references.citation: Neurol Sci. 2011 Feb;32(1):1-7
references.pmid: 21107876
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15091-6
references.pmid: 17015834
references.citation: Hum Mol Genet. 2011 Mar 15;20(6):1197-211
references.pmid: 21212098
references.citation: FASEB J. 2009 Aug;23(8):2478-89
references.pmid: 19276172
references.citation: Physiol Rev. 2011 Oct;91(4):1161-218
references.pmid: 22013209
references.citation: Toxicol Lett. 2009 Feb 10;184(3):186-91
references.pmid: 19063952
references.citation: Eur J Neurosci. 2010 Mar;31(6):967-77
references.pmid: 20377612
references.citation: Neurotoxicology. 2008 May;29(3):397-405
references.pmid: 18377993
references.citation: Brain. 2011 Jul;134(Pt 7):e178
references.pmid: 21349902
references.citation: Brain. 2004 Feb;127(Pt 2):420-30
references.pmid: 14662519
references.citation: Ann Neurol. 2003 Sep;54(3):283-6
references.pmid: 12953260
references.citation: Neurosci Lett. 2009 Nov 20;465(3):214-9
references.pmid: 19766170
references.citation: Ann Neurol. 2004 Jan;55(1):113-8
references.pmid: 14705119
references.citation: Neurochem Int. 2012 Jul;61(1):89-99
references.pmid: 22521774
references.citation: J Neurochem. 2011 May;117(3):357-8
references.pmid: 21413989
references.citation: Am J Respir Crit Care Med. 2008 Sep 15;178(6):592-604
references.pmid: 18556627
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12517-22
references.pmid: 16894167
references.citation: J Biol Chem. 2006 Apr 21;281(16):10816-24
references.pmid: 16517609