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Comparison of the behavioural and histological characteristics of the 6-OHDA and alpha-synuclein rat models of Parkinson's disease

Decressac, Mickael LU ; Mattsson, Bengt LU and Björklund, Anders LU (2012) In Experimental Neurology 235(1). p.306-315
Abstract
Development of relevant models of Parkinson's disease (PD) is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising targets for therapeutic intervention. To date, most pre-clinical studies have been performed in the well-established rodent and non-human primate models using injection of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). Overexpression of the disease-causing protein alpha-synuclein (alpha-syn), using adeno-associated viral (AAV) vectors, has provided a novel model that recapitulates many features of the human disease. In the present study we compared the AAV-alpha-syn rat model with models where the nigro-striatal... (More)
Development of relevant models of Parkinson's disease (PD) is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising targets for therapeutic intervention. To date, most pre-clinical studies have been performed in the well-established rodent and non-human primate models using injection of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). Overexpression of the disease-causing protein alpha-synuclein (alpha-syn), using adeno-associated viral (AAV) vectors, has provided a novel model that recapitulates many features of the human disease. In the present study we compared the AAV-alpha-syn rat model with models where the nigro-striatal pathway is lesioned by injection of 6-OHDA in the striatum (partial lesion) or the medial forebrain bundle (full lesion). Examination of the behavioural changes over time revealed a different progression and magnitude of the motor impairment. Interestingly, dopamine (DA) neuron loss is prominent in both the toxin and the AAV-alpha-syn models. However, alpha-syn overexpressing animals were seen to exhibit less cell and terminal loss for an equivalent level of motor abnormalities. Prominent and persistent axonal pathology is only observed in the alpha-syn rat model. We suggest that, while neuronal and terminal loss mainly accounts for the behavioural impairment in the toxin-based model, similar motor deficits result from the combination of cell death and dysfunction of the remaining nigro-striatal neurons in the AAV-alpha-syn model. While the two models have been developed to mimic DA neuron deficiency, they differ in their temporal and neuropathological characteristics, and replicate different aspects of the pathophysiology of the human disease. This study suggests that the AAV-alpha-syn model replicates the human pathology more closely than either of the other two 6-OHDA lesion models. (C) 2012 Elsevier Inc. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Behavioural test, Neurodegeneration, Axonopathy, AAV, Animal models
in
Experimental Neurology
volume
235
issue
1
pages
306 - 315
publisher
Academic Press
external identifiers
  • wos:000303430400032
  • scopus:84859889965
ISSN
0014-4886
DOI
10.1016/j.expneurol.2012.02.012
language
English
LU publication?
yes
id
7291a43c-9cce-4e46-81ac-07d6c5246474 (old id 2551694)
date added to LUP
2012-06-01 08:49:14
date last changed
2017-11-19 03:05:42
@article{7291a43c-9cce-4e46-81ac-07d6c5246474,
  abstract     = {Development of relevant models of Parkinson's disease (PD) is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising targets for therapeutic intervention. To date, most pre-clinical studies have been performed in the well-established rodent and non-human primate models using injection of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). Overexpression of the disease-causing protein alpha-synuclein (alpha-syn), using adeno-associated viral (AAV) vectors, has provided a novel model that recapitulates many features of the human disease. In the present study we compared the AAV-alpha-syn rat model with models where the nigro-striatal pathway is lesioned by injection of 6-OHDA in the striatum (partial lesion) or the medial forebrain bundle (full lesion). Examination of the behavioural changes over time revealed a different progression and magnitude of the motor impairment. Interestingly, dopamine (DA) neuron loss is prominent in both the toxin and the AAV-alpha-syn models. However, alpha-syn overexpressing animals were seen to exhibit less cell and terminal loss for an equivalent level of motor abnormalities. Prominent and persistent axonal pathology is only observed in the alpha-syn rat model. We suggest that, while neuronal and terminal loss mainly accounts for the behavioural impairment in the toxin-based model, similar motor deficits result from the combination of cell death and dysfunction of the remaining nigro-striatal neurons in the AAV-alpha-syn model. While the two models have been developed to mimic DA neuron deficiency, they differ in their temporal and neuropathological characteristics, and replicate different aspects of the pathophysiology of the human disease. This study suggests that the AAV-alpha-syn model replicates the human pathology more closely than either of the other two 6-OHDA lesion models. (C) 2012 Elsevier Inc. All rights reserved.},
  author       = {Decressac, Mickael and Mattsson, Bengt and Björklund, Anders},
  issn         = {0014-4886},
  keyword      = {Behavioural test,Neurodegeneration,Axonopathy,AAV,Animal models},
  language     = {eng},
  number       = {1},
  pages        = {306--315},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {Comparison of the behavioural and histological characteristics of the 6-OHDA and alpha-synuclein rat models of Parkinson's disease},
  url          = {http://dx.doi.org/10.1016/j.expneurol.2012.02.012},
  volume       = {235},
  year         = {2012},
}