title: α-Synuclein transgenic mice reveal compensatory increases in Parkinson's disease-associated proteins DJ-1 and parkin and have enhanced α-synuclein and PINK1 levels after rotenone treatment.
abstract: Parkinson's disease (PD) is a severe neurodegenerative disorder characterised by loss of dopaminergic neurons of the substantia nigra. The pathological hallmarks are cytoplasmic inclusions termed Lewy bodies consisting primarily of aggregated alpha-synuclein (alphaSN). Different lines of transgenic mice have been developed to model PD but have failed to recapitulate the hallmarks of this disease. Since treatment of rodents with the pesticide rotenone can reproduce nigrostriatal cell loss and other features of PD, we aimed to test chronic oral administration of rotenone to transgenic mice over-expressing human alphaSN with the A53T mutation. Initial assessment of this transgenic line for compensatory molecular changes indicated decreased brain beta-synuclein expression and significantly increased levels of the PD-associated oxidative stress response protein, DJ-1, and the E3 ubiquitin ligase enzyme, Parkin. Rotenone treatment of 30 mg/kg for 25 doses over a 35-day period was tolerated in the transgenic mice and resulted in decreased spontaneous locomotor movement and increased cytoplasmic alphaSN expression. The mitochondrial Parkinson's-associated PTEN-induced kinase 1 protein levels were also increased in transgenic mouse brain after rotenone treatment; there was no change in brain dopamine levels or nigrostriatal cell loss. These hA53T alphaSN transgenic mice provide a useful model for presymptomatic Parkinson's features and are valuable for study of associated compensatory changes in early Parkinson's disease stages.
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: George
authors.forename: Su San
authors.initials: SS
authors.lastname: Mok
authors.forename: Milawaty
authors.initials: M
authors.lastname: Nurjono
authors.forename: Scott
authors.initials: S
authors.lastname: Ayton
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.forename: Janetta G
authors.initials: JG
authors.lastname: Culvenor
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D012402:Rotenone / Q000633:toxicity*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*; D014475:Uncoupling Agents / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects*; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D015513:Oncogene Proteins; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D012402:Rotenone; D044767:Ubiquitin-Protein Ligases; D014475:Uncoupling Agents; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C503466:PARK7 protein, mouse
references.citation: Neurobiol Aging. 2006 Jun;27(6):848-56
references.pmid: 16006012
references.citation: Neurotox Res. 2007 Apr;11(3-4):219-40
references.pmid: 17449461
references.citation: Exp Neurol. 2008 Apr;210(2):788-92
references.pmid: 18295208
references.citation: J Biol Chem. 1999 Oct 8;274(41):28849-52
references.pmid: 10506125
references.citation: J Neurosci. 2002 Apr 15;22(8):3090-9
references.pmid: 11943812
references.citation: Am J Pathol. 2000 Aug;157(2):401-10
references.pmid: 10934145
references.citation: Neurology. 1998 May;50(5):1346-50
references.pmid: 9595985
references.citation: Biochem Biophys Res Commun. 2006 Nov 3;349(4):1294-300
references.pmid: 16978583
references.citation: J Neurochem. 1990 Mar;54(3):823-7
references.pmid: 2154550
references.citation: Exp Neurol. 2003 Jan;179(1):9-16
references.pmid: 12504863
references.citation: Science. 1983 Feb 25;219(4587):979-80
references.pmid: 6823561
references.citation: J Neurochem. 2007 Jun;101(6):1491-1504
references.pmid: 17459145
references.citation: Am J Pathol. 2007 Feb;170(2):658-66
references.pmid: 17255333
references.citation: J Neurosci. 2003 Apr 15;23(8):3095-9
references.pmid: 12716914
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73
references.pmid: 12084935
references.citation: Cell. 1998 Jun 12;93(6):973-83
references.pmid: 9635427
references.citation: Cell Tissue Res. 2004 Oct;318(1):225-41
references.pmid: 15258850
references.citation: Neurobiol Dis. 2006 May;22(2):404-20
references.pmid: 16439141
references.citation: J Biol Chem. 2002 Jan 18;277(3):1641-4
references.pmid: 11707429
references.citation: Am J Pathol. 1999 Oct;155(4):1173-81
references.pmid: 10514400
references.citation: Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
references.pmid: 12498954
references.citation: Behav Genet. 2000 May;30(3):171-82
references.pmid: 11105391
references.citation: Neurobiol Aging. 2008 Apr;29(4):586-97
references.pmid: 17316906
references.citation: Brain Res. 1988 May 10;448(1):150-7
references.pmid: 3260534
references.citation: Brain Res. 2000 Dec 8;885(2):283-8
references.pmid: 11102582
references.citation: Curr Opin Neurol. 2005 Aug;18(4):363-9
references.pmid: 16003110
references.citation: J Neurosci. 2000 Sep 1;20(17):6365-73
references.pmid: 10964942
references.citation: J Neurosci. 2003 Nov 26;23(34):10756-64
references.pmid: 14645467
references.citation: Nature. 2006 Jun 29;441(7097):1162-6
references.pmid: 16672981
references.citation: J Neurosci Res. 2007 Feb 15;85(3):681-91
references.pmid: 17171705
references.citation: Neuron. 2002 May 16;34(4):521-33
references.pmid: 12062037
references.citation: J Neurochem. 2008 Apr;105(1):18-33
references.pmid: 18221368
references.citation: Am J Pathol. 1998 Apr;152(4):879-84
references.pmid: 9546347
references.citation: Neurochem Res. 2008 May;33(5):902-11
references.pmid: 17999181
references.citation: Nat Neurosci. 2000 Dec;3(12):1301-6
references.pmid: 11100151
references.citation: J Biol Chem. 2006 Oct 6;281(40):29739-52
references.pmid: 16847063