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

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Author

Summary, in English

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.

Publishing year

2012

Language

English

Pages

306-315

Publication/Series

Experimental Neurology

Volume

235

Issue

1

Document type

Journal article

Publisher

Elsevier

Topic

  • Neurology

Keywords

  • Behavioural test
  • Neurodegeneration
  • Axonopathy
  • AAV
  • Animal models

Status

Published

Research group

  • Neurobiology

ISBN/ISSN/Other

  • ISSN: 0014-4886