title: 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.
abstract: 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 α-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 α-synuclein aggregates were formed in this model. This α-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 α-synuclein aggregation in the disease process.
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium.
authors.forename: Anke
authors.initials: A
authors.lastname: Van der Perren
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium.
authors.forename: Jaan
authors.initials: J
authors.lastname: Toelen
authors.affiliation: Division of Nuclear Medicine, Leuven University Hospital and KU Leuven, Leuven, Belgium.
authors.forename: Cindy
authors.initials: C
authors.lastname: Casteels
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium.
authors.forename: Francesca
authors.initials: F
authors.lastname: Macchi
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Van Rompuy
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sarre
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Casadei
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Department of Psychiatry, University of California San Diego, San Diego, USA.
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.affiliation: Biomedical MRI Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: Biomedical MRI Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Osorio Garcia
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.affiliation: Laboratory of Biological Psychology, Department of Psychology, KU Leuven, Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Laboratory for Radiopharmacy, Department of Pharmaceutical en Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.affiliation: Division of Nuclear Medicine, Leuven University Hospital and KU Leuven, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium. Electronic address: Veerle.Baekelandt@med.kuleuven.be.
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics*; D008137:Longitudinal Studies; D017551:Microdialysis; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D049268:Positron-Emission Tomography; D066329:Protein Aggregates; D013378:Substantia Nigra / Q000473:pathology; D013997:Time Factors; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D004298:Dopamine
keywords: Adeno-associated viral vectors; Animal model; PET imaging; Parkinson's disease; α-Synuclein