Human Molecular Genetics Advance Access published online on July 22, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg239
© 2003 by Oxford University Press
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1 Functional Genomics Department, Aventis Pharma S.A., 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France
* To whom correspondence should be addressed. E-mail: thomas.rooney{at}aventis.com.
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.
Article
Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse
2 INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France
3 Department of Research, Hospital Ramon y Cajal, Carretera de Colmenar km. 9,100, 28034 - Madrid, Spain
4 CNRS UMR 7593, Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France
5 CNS Department, Aventis Pharma S.A., 13 Quai Jules Guesde, F-94400 Vitry-sur-Seine, France
6 Department of Neurology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. de Reyes Católicos, 2. 28040 - Madrid, Spain
7 INSERM U289, Groupe Hopitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France; Département de Génétique, Cytogénétique et Embryologie, Groupe Hopitalier Pitié-Salpêtrière, AP-HP, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France
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