Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons.
|Title||Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons.|
|Publication Type||Journal Article|
|Year of Publication||2003|
|Authors||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 M-F, Maidment NT, Levine MS, Shen J|
|Journal||The Journal of biological chemistry|
|Date Published||2003 Oct 31|
|Keywords||Alleles, Animals, Behavior, Animal, Blotting, Western, Brain, Chromatography, High Pressure Liquid, Disease Models, Animal, Dopamine, Electrophysiology, Germ-Line Mutation, Mice, Mice, Transgenic, Models, Genetic, Neurons, Parkinson Disease, Receptors, Dopamine, substantia nigra, Time Factors, Ubiquitin-Protein Ligases|
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.
|Alternate Journal||J. Biol. Chem.|