Non-invasive imaging of neuropathology in a rat model of alpha-synuclein overexpression

Parkinson's disease is a neurodegenerative disorder affecting the doparminergic neurons in the substantia nigra. Aggregation of alpha-synuclein appears to play a central role in the pathogenesis. Novel animal models for neurodegeneration have been generated by lentiviral vector-mediated locoregional overexpression of disease-associated genes in the adult brain. We have used lentiviral vectors to overexpress a clinical mutant of a-synuclein, A30P, in the rat substantia nigra. This overexpression induced time-dependent cytoplasmic and neuritic accumulation of a-synuclein and neurodegeneration. A subgroup of the rats developed asymmetric rotational behavior after administration of amphetamine. In addition, these animals displayed reduced dopamine transporter binding visualized by I-123-FP-CIT microSPECT imaging. The behavioral and microSPECT data were validated by histological analysis. There was a strong correlation between the reduction of dopaminergic neurons in the substantia nigra and the reduction of dopamine transporter binding in the striatum. MicroSPECT imaging enables non-invasive imaging of the neurodegeneration allowing longitudinal follow-up in this new animal model for Parkinson's disease and the evaluation of neuroprotective drugs. (c) 2005 Elsevier Inc. All rights reserved.