Advanced

Development and characterisation of a novel rat model of Parkinson's disease induced by sequential intranigral administration of AAV-α-synuclein and the pesticide, rotenone.

Mulcahy, P.; O'Doherty, A.; Paucard, A.; O'Brien, T.; Kirik, Deniz LU and Dowd, E. (2012) In Neuroscience 203. p.170-179
Abstract
Modeling Parkinson's disease remains a major challenge for preclinical researchers, as existing models fail to reliably recapitulate all of the classic features of the disease, namely, the progressive emergence of a bradykinetic motor syndrome with underlying nigrostriatal alpha-synuclein protein accumulation and nigrostriatal neurodegeneration. One limitation of the existing models is that they are normally induced by a single neuropathological insult, whereas the human disease is thought to be multifactorial with genetic and environmental factors contributing to the disease pathogenesis. Thus, in order to develop a more relevant model, we sought to determine if administration of the Parkinson's disease-associated pesticide, rotenone,... (More)
Modeling Parkinson's disease remains a major challenge for preclinical researchers, as existing models fail to reliably recapitulate all of the classic features of the disease, namely, the progressive emergence of a bradykinetic motor syndrome with underlying nigrostriatal alpha-synuclein protein accumulation and nigrostriatal neurodegeneration. One limitation of the existing models is that they are normally induced by a single neuropathological insult, whereas the human disease is thought to be multifactorial with genetic and environmental factors contributing to the disease pathogenesis. Thus, in order to develop a more relevant model, we sought to determine if administration of the Parkinson's disease-associated pesticide, rotenone, into the substantia nigra of rats overexpressing the Parkinson's disease-associated protein, alpha-synuclein, could reliably model the triad of classic features of the human disease. To do so, rats underwent stereotaxic surgery for unilateral delivery of the adenoassociated virus (AAV)-alpha-synuclein into the substantia nigra. This was followed 13 weeks later by delivery of rotenone into the same site. 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 rats treated with either AAV-alpha-synuclein or rotenone developed significant motor dysfunction with underlying nigrostriatal neurodegeneration. However, when the genetic and environmental insults were sequentially administered, the detrimental impact of the combined insults on motor performance and nigrostriatal integrity was significantly greater than the impact of either insult alone. This indicates that sequential exposure to relevant genetic and environmental insults is a valid approach to modeling human Parkinson's disease in the rat. 2011 IBRO. Published by Elsevier Ltd. All rights reserved. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Parkinson's disease, animal models, AAV-alpha-synuclein, rotenone, motor, function
in
Neuroscience
volume
203
pages
170 - 179
publisher
Elsevier
external identifiers
  • wos:000300757300016
  • scopus:84856440571
ISSN
1873-7544
DOI
10.1016/j.neuroscience.2011.12.011
language
English
LU publication?
yes
id
097f93a5-bee4-44c2-b1e8-2784d240134b (old id 2390970)
date added to LUP
2012-04-02 09:26:47
date last changed
2017-06-11 03:03:48
@article{097f93a5-bee4-44c2-b1e8-2784d240134b,
  abstract     = {Modeling Parkinson's disease remains a major challenge for preclinical researchers, as existing models fail to reliably recapitulate all of the classic features of the disease, namely, the progressive emergence of a bradykinetic motor syndrome with underlying nigrostriatal alpha-synuclein protein accumulation and nigrostriatal neurodegeneration. One limitation of the existing models is that they are normally induced by a single neuropathological insult, whereas the human disease is thought to be multifactorial with genetic and environmental factors contributing to the disease pathogenesis. Thus, in order to develop a more relevant model, we sought to determine if administration of the Parkinson's disease-associated pesticide, rotenone, into the substantia nigra of rats overexpressing the Parkinson's disease-associated protein, alpha-synuclein, could reliably model the triad of classic features of the human disease. To do so, rats underwent stereotaxic surgery for unilateral delivery of the adenoassociated virus (AAV)-alpha-synuclein into the substantia nigra. This was followed 13 weeks later by delivery of rotenone into the same site. 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 rats treated with either AAV-alpha-synuclein or rotenone developed significant motor dysfunction with underlying nigrostriatal neurodegeneration. However, when the genetic and environmental insults were sequentially administered, the detrimental impact of the combined insults on motor performance and nigrostriatal integrity was significantly greater than the impact of either insult alone. This indicates that sequential exposure to relevant genetic and environmental insults is a valid approach to modeling human Parkinson's disease in the rat. 2011 IBRO. Published by Elsevier Ltd. All rights reserved.},
  author       = {Mulcahy, P. and O'Doherty, A. and Paucard, A. and O'Brien, T. and Kirik, Deniz and Dowd, E.},
  issn         = {1873-7544},
  keyword      = {Parkinson's disease,animal models,AAV-alpha-synuclein,rotenone,motor,function},
  language     = {eng},
  pages        = {170--179},
  publisher    = {Elsevier},
  series       = {Neuroscience},
  title        = {Development and characterisation of a novel rat model of Parkinson's disease induced by sequential intranigral administration of AAV-α-synuclein and the pesticide, rotenone.},
  url          = {http://dx.doi.org/10.1016/j.neuroscience.2011.12.011},
  volume       = {203},
  year         = {2012},
}