title: BAG1 is neuroprotective in in vivo and in vitro models of Parkinson's disease.
abstract: Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington's disease. In the context of Parkinson's disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson's disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson's disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson's disease.
authors.affiliation: Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Sande, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Kermer
authors.forename: Anja
authors.initials: A
authors.lastname: Köhn
authors.forename: Marlena
authors.initials: M
authors.lastname: Schnieder
authors.forename: Paul
authors.initials: P
authors.lastname: Lingor
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Jan
authors.initials: J
authors.lastname: Liman
authors.forename: Christoph Peter
authors.initials: CP
authors.lastname: Dohm
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020267:MPTP Poisoning / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D012402:Rotenone / Q000633:toxicity; D013378:Substantia Nigra / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D051844:alpha-Synuclein; D012402:Rotenone; D016627:Oxidopamine
references.citation: Mol Cell Biol. 1989 Mar;9(3):1049-59
references.pmid: 2657385
references.citation: Ann N Y Acad Sci. 2003 Jun;991:189-98
references.pmid: 12846987
references.citation: Brain Res Bull. 1992 Nov;29(5):699-701
references.pmid: 1422867
references.citation: PLoS One. 2008 Apr 02;3(4):e1867
references.pmid: 18382657
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10918-23
references.pmid: 11535810
references.citation: EMBO J. 2009 Apr 8;28(7):889-901
references.pmid: 19229298
references.citation: Cancer Res. 1998 Jul 15;58(14):3116-31
references.pmid: 9679980
references.citation: Cell. 1995 Jan 27;80(2):279-84
references.pmid: 7834747
references.citation: J Biol Chem. 1996 Feb 9;271(6):3317-23
references.pmid: 8621737
references.citation: J Biol Chem. 2000 Feb 18;275(7):4613-7
references.pmid: 10671488
references.citation: J Neurochem. 2008 Jul;106(2):529-40
references.pmid: 18410502
references.citation: Neurology. 2000;54(11 Suppl 5):S21-3
references.pmid: 10854357
references.citation: J Neurosci. 1998 Oct 15;18(20):8145-52
references.pmid: 9763461
references.citation: PLoS One. 2009;4(5):e5515
references.pmid: 19436756
references.citation: J Cell Biol. 2010 Feb 22;188(4):505-13
references.pmid: 20156966
references.citation: Proc Natl Acad Sci U S A. 1998 May 12;95(10):5789-94
references.pmid: 9576963
references.citation: NeuroRx. 2005 Jul;2(3):484-94
references.pmid: 16389312
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2837-42
references.pmid: 11226327
references.citation: J Virol. 2004 Jul;78(13):6808-17
references.pmid: 15194756
references.citation: Cold Spring Harb Perspect Med. 2012 May;2(5):a009423
references.pmid: 22553500
references.citation: J Biol Chem. 2004 Dec 24;279(52):54380-6
references.pmid: 15492001
references.citation: Nat Cell Biol. 2000 Jul;2(7):E115-9
references.pmid: 10878819
references.citation: Neurodegener Dis. 2008;5(6):321-38
references.pmid: 18309232
references.citation: J Neural Transm (Vienna). 2000;107(3):281-93
references.pmid: 10821437
references.citation: Cell Death Differ. 2002 Apr;9(4):405-13
references.pmid: 11965493
references.citation: Brain. 2008 Oct;131(Pt 10):2606-19
references.pmid: 18757464
references.citation: Eur J Neurosci. 2006 Dec;24(11):3174-82
references.pmid: 17156378
references.citation: Curr Biol. 2001 Oct 16;11(20):1569-77
references.pmid: 11676916
references.citation: Prog Neurobiol. 2001 Oct;65(2):135-72
references.pmid: 11403877
references.citation: Neurosci Lett. 1996 Dec 27;221(1):69-71
references.pmid: 9014183
references.citation: J Biol Chem. 2004 Jun 11;279(24):25497-502
references.pmid: 15044495
references.citation: J Neurochem. 2009 Nov;111(3):801-7
references.pmid: 19712056
references.citation: J Biol Chem. 2005 Jun 24;280(25):23727-34
references.pmid: 15845543
references.citation: Nat Cell Biol. 2001 Oct;3(10):E237-41
references.pmid: 11584289
references.citation: J Biol Chem. 2006 Mar 3;281(9):5373-82
references.pmid: 16361258
references.citation: Life Sci. 1985 Jul 1;36(26):2503-8
references.pmid: 2861548
references.citation: Hum Mol Genet. 2002 Oct 1;11(20):2395-407
references.pmid: 12351575
references.citation: Biochim Biophys Acta. 2001 Jul 2;1506(1):79-87
references.pmid: 11418099
references.citation: J Neurochem. 1996 May;66(5):2004-10
references.pmid: 8780029
references.citation: Mol Cell Biol. 2005 May;25(9):3715-25
references.pmid: 15831476
references.citation: Neuroscience. 1997 Apr;77(4):1037-48
references.pmid: 9130785