Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1.
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.
Dong
Zhizhong
Z
Institute of Molecular Biology, University of Zurich, 8057 Zurich, Switzerland.
Ferger
Boris
B
Paterna
Jean-Charles
JC
Vogel
Denise
D
Furler
Sven
S
Osinde
Maribel
M
Feldon
Joram
J
Büeler
Hansruedi
H
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D018797:Cell Cycle Proteins; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D000229:Dependovirus / Q000235:genetics; D004298:Dopamine / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D009154:Mutation; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D010957:Plasmids / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D058112:Septins; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D019805:alpha-Methyltyrosine; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C109366:SEPTIN5 protein, human; C491613:Septin5 protein, rat; D058112:Septins; D004298:Dopamine