Dopamine depletion impairs precursor cell proliferation in Parkinson disease

Abstract

Cerebral dopamine depletion is the hallmark of Parkinson disease. Because dopamine modulates ontogenetic neurogenesis, depletion of dopamine might affect neural precursors in the subependymal zone and subgranular zone of the adult brain. Here we provide ultrastructural evidence showing that highly proliferative precursors in the adult subependymal zone express dopamine receptors and receive dopaminergic afferents. Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone. Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors. Experiments with neural precursors from the adult subependymal zone grown as neurosphere cultures confirm that activation of D2L receptors directly increases the proliferation of these precursors. Consistently, the numbers of proliferating cells in the subependymal zone and neural precursor cells in the subgranular zone and olfactory bulb are reduced in postmortem brains of individuals with Parkinson disease. These observations suggest that the generation of neural precursor cells is impaired in Parkinson disease as a consequence of dopaminergic denervation.

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Figure 1: Dopaminergic innervation in the adult mammalian subependymal zone.
Figure 2: Subependymal zone proliferation parallels loss and regeneration of dopaminergic fibers.
Figure 3: Persistent dopaminergic denervation decreases and dopaminergic pharmacotherapy restores subependymal zone proliferation.
Figure 4: Activation of the D2L receptor stimulates precursor cell proliferation in neurosphere cultures.
Figure 5: Dopaminergic denervation reduces the proliferation of EGFR+ cells and the number of A-cells.
Figure 6: Dopaminergic denervation reduces the number of newborn olfactory neurons.
Figure 7: Dopaminergic innervation modulates cell proliferation in the hippocampus.
Figure 8: Reduced number of precursor cells in individuals with Parkinson disease (PD).

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Acknowledgements

We thank B. Mathieu and C. Cappe for technical assistance and M. Ruberg for discussions. This work was funded by the Institut National de la Santé et de la Recherche Médicale, the Deutsche Forschungsgemeinschaft (ho2402/2-1), the Fondation pour la Recherche Médicale (ACE20030307094), the Peter Hofmann research project and the Parkinson's Disease Foundation–National Parkinson Foundation Joint Research Grant Program.

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Correspondence to Günter U Höglinger.

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Höglinger, G., Rizk, P., Muriel, M. et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 7, 726–735 (2004). https://doi.org/10.1038/nn1265

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