Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse.
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.
Itier
Jean-Michel
JM
Functional Genomics Department, Aventis Pharma SA, Vitry-sur-Seine, France.
Ibanez
Pablo
P
Mena
Maria Angeles
MA
Abbas
Nacer
N
Cohen-Salmon
Charles
C
Bohme
Georg Andrees
GA
Laville
Michel
M
Pratt
Jeremy
J
Corti
Olga
O
Pradier
Laurent
L
Ret
Gwenaelle
G
Joubert
Chantal
C
Periquet
Magali
M
Araujo
Francisco
F
Negroni
Julia
J
Casarejos
Maria Jose
MJ
Canals
Santiago
S
Solano
Rosa
R
Serrano
Alba
A
Gallego
Eva
E
Sanchez
Marina
M
Denefle
Patrice
P
Benavides
Jesus
J
Tremp
Gunter
G
Rooney
Thomas A
TA
Brice
Alexis
A
Garcia de Yebenes
Justo
J
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
D002395:Catecholamines; D004791:Enzyme Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D019805:alpha-Methyltyrosine; D008995:Monoamine Oxidase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine