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Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons.

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.

Pubmed ID: 12930822


  • 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
  • Shen J


The Journal of biological chemistry

Publication Data

October 31, 2003

Associated Grants


Mesh Terms

  • 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