title: Unaltered striatal dopamine release levels in young Parkin knockout, Pink1 knockout, DJ-1 knockout and LRRK2 R1441G transgenic mice.
abstract: Parkinson's disease (PD) is one of the most prevalent neurodegenerative brain diseases; it is accompanied by extensive loss of dopamine (DA) neurons of the substantia nigra that project to the putamen, leading to impaired motor functions. Several genes have been associated with hereditary forms of the disease and transgenic mice have been developed by a number of groups to produce animal models of PD and to explore the basic functions of these genes. Surprisingly, most of the various mouse lines generated such as Parkin KO, Pink1 KO, DJ-1 KO and LRRK2 transgenic have been reported to lack degeneration of nigral DA neuron, one of the hallmarks of PD. However, modest impairments of motor behavior have been reported, suggesting the possibility that the models recapitulate at least some of the early stages of PD, including early dysfunction of DA axon terminals. To further evaluate this possibility, here we provide for the first time a systematic comparison of DA release in four different mouse lines, examined at a young age range, prior to potential age-dependent compensations. Using fast scan cyclic voltammetry in striatal sections prepared from young, 6-8 weeks old mice, we examined sub-second DA overflow evoked by single pulses and action potential trains. Unexpectedly, none of the models displayed any dysfunction of DA overflow or reuptake. These results, compatible with the lack of DA neuron loss in these models, suggest that molecular dysfunctions caused by the absence or mutation of these individual genes are not sufficient to perturb the function and survival of mouse DA neurons.
authors.affiliation: Departments of pharmacology and neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Sanchez
authors.affiliation: Departments of pharmacology and neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Rafael K
authors.initials: RK
authors.lastname: Varaschin
authors.affiliation: School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Büeler
authors.affiliation: Department of cellular and molecular medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Marcogliese
authors.affiliation: Department of cellular and molecular medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.affiliation: Departments of pharmacology and neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Louis-Eric
authors.initials: LE
authors.lastname: Trudeau
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D055664:Electrochemical Techniques; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D017072:Neostriatum; D015513:Oncogene Proteins / Q000172:deficiency* / Q000378:metabolism; D054464:Peroxiredoxins / Q000172:deficiency* / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000172:deficiency* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D009435:Synaptic Transmission; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015513:Oncogene Proteins; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C495279:Lrrk2 protein, mouse; C503466:PARK7 protein, mouse
references.citation: Cold Spring Harb Perspect Med. 2012 Jul;2(7):a009290
references.pmid: 22762023
references.citation: EMBO J. 2012 Jun 26;31(14):3038-62
references.pmid: 22735187
references.citation: PLoS One. 2011 Jan 13;6(1):e16038
references.pmid: 21249202
references.citation: J Biol Chem. 2010 Apr 9;285(15):11740-52
references.pmid: 20164189
references.citation: PLoS One. 2011;6(5):e20402
references.pmid: 21647367
references.citation: J Neurosci. 2013 Oct 23;33(43):17095-107
references.pmid: 24155314
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6400-5
references.pmid: 23509287
references.citation: Mol Neurodegener. 2012 May 30;7:25
references.pmid: 22647713
references.citation: J Biol Chem. 2003 Oct 31;278(44):43628-35
references.pmid: 12930822
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):15918-23
references.pmid: 23019375
references.citation: Trends Neurosci. 2012 Jun;35(6):364-72
references.pmid: 22578891
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):E4016-25
references.pmid: 24082145
references.citation: Neurotherapeutics. 2012 Apr;9(2):297-314
references.pmid: 22350713
references.citation: J Cell Sci. 2011 Apr 1;124(Pt 7):1115-25
references.pmid: 21385841
references.citation: J Cell Biol. 2010 Apr 19;189(2):211-21
references.pmid: 20404107
references.citation: J Neurochem. 2009 Nov;111(3):696-702
references.pmid: 19694908
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5215-20
references.pmid: 15784737
references.citation: Exp Neurol. 2012 Oct;237(2):318-34
references.pmid: 22750327
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 13;108 Suppl 3:15542-8
references.pmid: 21383190
references.citation: Neurodegener Dis. 2008;5(3-4):114-7
references.pmid: 18322366
references.citation: Neuron. 2012 Sep 6;75(5):762-77
references.pmid: 22958818
references.citation: J Neurosci. 2010 Feb 3;30(5):1788-97
references.pmid: 20130188
references.citation: J Neurosci Methods. 2011 Nov 15;202(2):158-64
references.pmid: 21392532
references.citation: Neurobiol Dis. 2010 Dec;40(3):503-17
references.pmid: 20659558
references.citation: Nat Neurosci. 2009 Jul;12(7):826-8
references.pmid: 19503083
references.citation: Neuron. 2005 Feb 17;45(4):489-96
references.pmid: 15721235
references.citation: Neurobiol Dis. 2013 Sep;57:38-46
references.pmid: 22776331
references.citation: Neuron. 2000 Jan;25(1):239-52
references.pmid: 10707987
references.citation: Hum Mol Genet. 2003 Sep 15;12(18):2277-91
references.pmid: 12915482
references.citation: Biochim Biophys Acta. 2011 Jun;1812(6):674-84
references.pmid: 21421046
references.citation: Prog Neurobiol. 2013 Jul-Aug;106-107:17-32
references.pmid: 23643800
references.citation: Neuron. 2011 Jul 14;71(1):35-48
references.pmid: 21745636
references.citation: Mol Cell. 2009 Mar 13;33(5):627-38
references.pmid: 19285945
references.citation: Adv Exp Med Biol. 2012;970:553-72
references.pmid: 22351072
references.citation: Nature. 2006 Jun 29;441(7097):1162-6
references.pmid: 16672981
references.citation: Hum Mol Genet. 2010 Oct 1;19(19):3734-46
references.pmid: 20639397
references.citation: J Neurochem. 2009 Jul;110(2):613-21
references.pmid: 19457102
references.citation: PLoS Biol. 2010 Jan 26;8(1):e1000298
references.pmid: 20126261
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14622-7
references.pmid: 19667187
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3228-33
references.pmid: 10077666
references.citation: Neuron. 2010 Jun 10;66(5):646-61
references.pmid: 20547124
references.citation: Neurobiol Dis. 2007 Aug;27(2):141-50
references.pmid: 17560790
references.citation: Science. 2013 Apr 26;340(6131):471-5
references.pmid: 23620051
references.citation: J Neurosci. 2009 Feb 18;29(7):1962-76
references.pmid: 19228951
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1716-21
references.pmid: 18218782
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11441-6
references.pmid: 17563363
references.citation: Mol Ther. 2007 Apr;15(4):698-704
references.pmid: 17299411
references.citation: PLoS One. 2012;7(5):e36397
references.pmid: 22570709
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83
references.pmid: 19966284
references.citation: Brain Res. 2010 Sep 17;1352:214-22
references.pmid: 20620130