[PDF][PDF] Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1

MS Goldberg, A Pisani, M Haburcak, TA Vortherms… - Neuron, 2005 - cell.com
MS Goldberg, A Pisani, M Haburcak, TA Vortherms, T Kitada, C Costa, Y Tong, G Martella…
Neuron, 2005cell.com
The manifestations of Parkinson's disease are caused by reduced dopaminergic innervation
of the striatum. Loss-of-function mutations in the DJ-1 gene cause early-onset familial
parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we
generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1−/− mice
had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine
overflow in the striatum was markedly reduced, primarily as a result of increased reuptake …
Summary
The manifestations of Parkinson's disease are caused by reduced dopaminergic innervation of the striatum. Loss-of-function mutations in the DJ-1 gene cause early-onset familial parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1−/− mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake. Nigral neurons lacking DJ-1 were less sensitive to the inhibitory effects of D2 autoreceptor stimulation. Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1−/− mice, but long-term depression (LTD) was absent. The LTD deficit was reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1−/− mice displayed hypoactivity in the open field. Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptor-mediated functions.
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