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PMID:12930822
Citation |
Goldberg, MS, Fleming, SM, Palacino, JJ, Cepeda, C, Lam, HA, Bhatnagar, A, Meloni, EG, Wu, N, Ackerson, LC, Klapstein, GJ, Gajendiran, M, Roth, BL, Chesselet, MF, Maidment, NT, Levine, MS and Shen, J (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem. 278:43628-35 |
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Abstract |
Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady-state levels of CDCrel-1, synphilin-1, and alpha-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice. |
Links |
PubMed Online version:10.1074/jbc.M308947200 |
Keywords |
Alleles; Animals; Behavior, Animal; Blotting, Western; Brain/metabolism; Brain/pathology; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine/metabolism; Electrophysiology; Germ-Line Mutation; Mice; Mice, Transgenic; Models, Genetic; Neurons/metabolism; Parkinson Disease/genetics; Receptors, Dopamine/metabolism; Substantia Nigra/metabolism; Time Factors; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/physiology |
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