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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

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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 α-synuclein (αSN). 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 αSN with the A53T mutation. Initial assessment of this transgenic line for compensatory molecular changes indicated decreased brain β-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 αSN 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 αSN 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.

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Acknowledgements

We sincerely thank B. Etherton for gavaging the mice. We thank V.M. Lee and J.Q. Trojanowski for the transgenic mouse line. We thank J. Anderson for antibody 11A5, P.J. Kahle for Ab 7544 and T. Iwatsubo for mAb LB509. For assistance with immunohistochemistry, we thank L. Leone and J. George. These studies were supported by the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Department of Pathology, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia

    Sonia George, Su San Mok, Colin L. Masters, Qiao-Xin Li & Janetta G. Culvenor

  2. The Centre for Neuroscience, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia

    Sonia George, Su San Mok, David I. Finkelstein, Qiao-Xin Li & Janetta G. Culvenor

  3. The Mental Health Research Institute of Victoria, Parkville, Melbourne, Victoria, 3052, Australia

    Sonia George, Su San Mok, Milawaty Nurjono, Scott Ayton, David I. Finkelstein, Colin L. Masters, Qiao-Xin Li & Janetta G. Culvenor

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  1. Sonia George
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  2. Su San Mok
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  3. Milawaty Nurjono
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Correspondence to Janetta G. Culvenor.

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George, S., Mok, S.S., Nurjono, M. et al. 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. J Mol Neurosci 42, 243–254 (2010). https://doi.org/10.1007/s12031-010-9378-1

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  • DOI: https://doi.org/10.1007/s12031-010-9378-1

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