title: Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons.
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.
authors.affiliation: Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Fleming
authors.forename: James J
authors.initials: JJ
authors.lastname: Palacino
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.forename: Hoa A
authors.initials: HA
authors.lastname: Lam
authors.forename: Anushree
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Edward G
authors.initials: EG
authors.lastname: Meloni
authors.forename: Nanping
authors.initials: N
authors.lastname: Wu
authors.forename: Larry C
authors.initials: LC
authors.lastname: Ackerson
authors.forename: Gloria J
authors.initials: GJ
authors.lastname: Klapstein
authors.forename: Mahadevan
authors.initials: M
authors.lastname: Gajendiran
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Chesselet
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Maidment
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
mesh_terms: D000483:Alleles; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004594:Electrophysiology; D018095:Germ-Line Mutation; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics; D011954:Receptors, Dopamine / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology*
chemical_list: D011954:Receptors, Dopamine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine