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.
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.
George
Sonia
S
Department of Pathology, The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
Mok
Su San
SS
Nurjono
Milawaty
M
Ayton
Scott
S
Finkelstein
David I
DI
Masters
Colin L
CL
Li
Qiao-Xin
QX
Culvenor
Janetta G
JG
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
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
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