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The behavioural and neuropathological impact of intranigral AAV-alpha-synuclein is exacerbated by systemic infusion of the Parkinson's disease-associated pesticide, rotenone, in rats

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Author

  • Padraig Mulcahy
  • Aideen O'Doherty
  • Alexia Paucard
  • Timothy O'Brien
  • Deniz Kirik
  • Eilis Dowd

Summary, in English

Despite the widely held belief that Parkinson's disease is caused by both underlying genetics and exposure to environmental risk factors, it is still widely modelled in preclinical models using a single genetic or neurotoxic insult. This single-insult approach has resulted in a variety of models that are limited with respect to their aetiological, construct, face and/or predictive validity. Thus, the aim of the current study was to investigate the interplay between genes and the environment as an alternative approach to modelling Parkinson's disease. To do so, rats underwent stereotaxic surgery for unilateral delivery of the Parkinson's disease-associated gene, alpha-synuclein, into the substantia nigra (using AAV vectors). This was followed 13 weeks later by subcutaneous implantation of an osmotic minipump delivering the Parkinson's disease-associated pesticide, rotenone (2.5 mg kg(-1) day(-1) for 4 weeks): The effect of the genetic and environmental insults alone or in combination on lateralised motor performance (Corridor, Stepping and Whisker Tests), nigrostriatal integrity (tyrosine hydroxylase immunohistochemistry) and alpha-synucleinopathy (alpha-synuclein immunohistochemistry) was assessed. We found that exposing AAV-alpha-synuclein-treated rats to rotenone led to a model in which the classical Parkinson's disease triad of progressive motor dysfunction, nigrostriatal neurodegeneration and alpha-synucleinopathy was evident. However, delivering rotenone systemically was also associated with bilateral motor dysfunction and loss of body weight. Thus, although we have shown that Parkinson's disease can be modelled in experimental animals by combined exposure to both genetic and environmental risk factors, this approach is limited by systemic toxicity of the pesticide rotenone. Direct intracerebral delivery of rotenone may be more useful in longer-term studies as we have previously shown that it overcomes this limitation. (C) 2013 Elsevier B.V. All rights reserved.

Publishing year

2013

Language

English

Pages

6-15

Publication/Series

Behavioural Brain Research

Volume

243

Document type

Journal article

Publisher

Elsevier

Topic

  • Neurosciences

Keywords

  • Parkinson's disease
  • Animal models
  • AAV-alpha-synuclein
  • Rotenone
  • Motor
  • function

Status

Published

Research group

  • Brain Repair and Imaging in Neural Systems (BRAINS)

ISBN/ISSN/Other

  • ISSN: 0166-4328