Longitudinal follow-up and characterization of a robust rat model for Parkinson's disease based on overexpression of alpha-synuclein with adeno-associated viral vectors

NEUROBIOLOGY OF AGING

卷:36

Article

Van der Perren, Anke¹  Toelen, Jaan²  Casteels, Cindy^3,4  Macchi, Francesca¹  Van Rompuy, Anne-Sophie¹  Sarre, Sophie⁵  Nuber, Silke⁶  Himmelreich, Uwe⁷  Garcia, Maria Isabel Osorio⁷  Michotte, Yvette⁵  D'Hooge, Rudi⁸  Bormans, Guy⁹  Van Laere, Koen^3,4  Gijsbers, Rik^2,10  Van den Haute, Chris^1,10  Debyser, Zeger^2,10  Baekelandt, Veerle^1,10 

[1] Katholieke Univ Leuven, Dept Neurosci, Lab Neurobiol & Gene Therapy, B-3000 Leuven, Flanders, Belgium

[2] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Lab Mol Virol & Gene Therapy, B-3000 Leuven, Flanders, Belgium

[3] Leuven Univ Hosp, Div Nucl Med, Leuven, Belgium

[4] Katholieke Univ Leuven, B-3000 Leuven, Flanders, Belgium

[5] Vrije Univ Brussel, Dept Pharmaceut Chem & Drug Anal, Brussels, Belgium

[6] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA

[7] Katholieke Univ Leuven, Biomed MRI Unit, Dept Imaging & Pathol, B-3000 Leuven, Flanders, Belgium

[8] Katholieke Univ Leuven, Dept Psychol, Lab Biol Psychol, B-3000 Leuven, Flanders, Belgium

[9] Katholieke Univ Leuven, Dept Pharmaceut Pharmacol Sci, Lab Radiopharmacy, B-3000 Leuven, Flanders, Belgium

[10] Katholieke Univ Leuven, Leuven Viral Vector Core, B-3000 Leuven, Flanders, Belgium

关键词: Adeno-associated viral vectors;    Animal model;    alpha-Synuclein;    Parkinson's disease;    PET imaging;   

DOI  :  10.1016/j.neurobiolaging.2014.11.015

来源: Elsevier

【 摘 要 】

Testing of new therapeutic strategies for Parkinson's disease (PD) is currently hampered by the lack of relevant and reproducible animal models. Here, we developed a robust rat model for PD by injection of adeno-associated viral vectors (rAAV2/7) encoding a-synuclein into the substantia nigra, resulting in reproducible nigrostriatal pathology and behavioral deficits in a 4-week time period. Progressive dopaminergic dysfunction was corroborated by histopathologic and biochemical analysis, motor behavior testing and in vivo microdialysis. L-DOPA treatment was found to reverse the behavioral phenotype. Non-invasive positron emission tomography imaging and magnetic resonance spectroscopy allowed longitudinal monitoring of neurodegeneration. In addition, insoluble a-synuclein aggregates were formed in this model. This a-synuclein rat model shows improved face and predictive validity, and therefore offers the possibility to reliably test novel therapeutics. Furthermore, it will be of great value for further research into the molecular pathogenesis of PD and the importance of a-synuclein aggregation in the disease process. (C) 2015 Elsevier Inc. All rights reserved.

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