Dopamine-Dependent Neurodegeneration in Rats Induced by Viral Vector-Mediated Overexpression of the Parkin Target Protein, CDCrel-1

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-10, Vol.100 (21), p.12438-12443
• Main Authors: Dong, Zhizhong, Ferger, Boris, Paterna, Jean-Charles, Vogel, Denise, Furler, Sven, Osinde, Maribel, Feldon, Joram, Büeler, Hansruedi
• Format: Article
• Language: English
• Subjects: alpha-Methyltyrosine - pharmacology; Animals; Animals, Genetically Modified; Base Sequence; Biological Sciences; Cell Cycle Proteins; Cerebral hemispheres; Corpus Striatum - pathology; Corpus Striatum - physiopathology; Dependovirus - genetics; Dopamine - physiology; Enzyme Inhibitors - pharmacology; Gene Expression; Gene Transfer Techniques; Genes; Genetic mutation; Genetic Vectors; Humans; Male; Mutation; Nerve Degeneration - etiology; Nerve Degeneration - genetics; Nerve Degeneration - physiopathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurology; Neurons; Neuroscience; Parkinsonian Disorders - etiology; Parkinsonian Disorders - genetics; Parkinsonian Disorders - physiopathology; PC12 Cells; Plasmids - genetics; Proteins; Rats; Rats, Wistar; Rodents; Secretion; Septins; Substantia Nigra - pathology; Substantia Nigra - physiopathology; Transgenes; Tyrosine 3-Monooxygenase - antagonists & inhibitors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - physiology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2132992100

Mutations in the parkin gene are linked to autosomal-recessive juvenile parkinsonism (AR-JP). Parkin functions as a ubiquitin protein ligase in the degradation of several proteins, including the neuron-specific septin CDCrel-1. AR-JP-associated parkin mutations inhibit ubiquitination and degradation of CDCrel-1 and other parkin target proteins. Here we show that recombinant adeno-associated virus-mediated CDCrel-1 gene transfer to the substantia nigra of rats results in a rapid onset (6-10 days) of nigral and striatal CDCrel-1 expression that is followed by a progressive loss of nigral dopaminergic neurons and a decline of the striatal dopamine levels. In contrast, neurons of the globus pallidus are spared from CDCrel-1 toxicity. Furthermore, CDCrel-1 inhibits the release of dopamine from stably-transfected PC12 cells, and pharmacological inhibition of tyrosine hydroxylase and dopamine synthesis in rats prevents CDCrel-1-induced nigral neurodegeneration. These results show that CDCrel-1 overexpression exerts dopamine-dependent neurotoxicity and suggest that inhibition of dopamine secretion by CDCrel-1 may contribute to the development of AR-JP.