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

TitleParkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons.
Publication TypeJournal Article
Year of Publication2003
AuthorsGoldberg, 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
JournalThe Journal of biological chemistry
Volume278
Issue44
Pagination43628-35
Date Published2003 Oct 31
ISSN0021-9258
KeywordsAlleles, 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
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.

DOI10.1042/AN20110063
Alternate JournalJ. Biol. Chem.