title: Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse.
abstract: Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.
authors.affiliation: Functional Genomics Department, Aventis Pharma SA, Vitry-sur-Seine, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Itier
authors.forename: Pablo
authors.initials: P
authors.lastname: Ibanez
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Mena
authors.forename: Nacer
authors.initials: N
authors.lastname: Abbas
authors.forename: Charles
authors.initials: C
authors.lastname: Cohen-Salmon
authors.forename: Georg Andrees
authors.initials: GA
authors.lastname: Bohme
authors.forename: Michel
authors.initials: M
authors.lastname: Laville
authors.forename: Jeremy
authors.initials: J
authors.lastname: Pratt
authors.forename: Olga
authors.initials: O
authors.lastname: Corti
authors.forename: Laurent
authors.initials: L
authors.lastname: Pradier
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Ret
authors.forename: Chantal
authors.initials: C
authors.lastname: Joubert
authors.forename: Magali
authors.initials: M
authors.lastname: Periquet
authors.forename: Francisco
authors.initials: F
authors.lastname: Araujo
authors.forename: Julia
authors.initials: J
authors.lastname: Negroni
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Casarejos
authors.forename: Santiago
authors.initials: S
authors.lastname: Canals
authors.forename: Rosa
authors.initials: R
authors.lastname: Solano
authors.forename: Alba
authors.initials: A
authors.lastname: Serrano
authors.forename: Eva
authors.initials: E
authors.lastname: Gallego
authors.forename: Marina
authors.initials: M
authors.lastname: Sanchez
authors.forename: Patrice
authors.initials: P
authors.lastname: Denefle
authors.forename: Jesus
authors.initials: J
authors.lastname: Benavides
authors.forename: Gunter
authors.initials: G
authors.lastname: Tremp
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rooney
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Justo
authors.initials: J
authors.lastname: Garcia de Yebenes
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D002395:Catecholamines / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism* / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D005260:Female; D020868:Gene Silencing; D006720:Homozygote; D007438:Introns; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000378:metabolism*; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D019805:alpha-Methyltyrosine / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D004791:Enzyme Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D019805:alpha-Methyltyrosine; D008995:Monoamine Oxidase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine