Dopamine depletion impairs precursor cell proliferation in Parkinson disease.
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.
Höglinger
Günter U
GU
INSERM U289 Hôpital de la Salpetrière, F-75651 Paris, France. gunter@ccr.jussieu.fr
Rizk
Pamela
P
Muriel
Marie P
MP
Duyckaerts
Charles
C
Oertel
Wolfgang H
WH
Caille
Isabelle
I
Hirsch
Etienne C
EC
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000172:deficiency* / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D004805:Ependyma / Q000166:cytology / Q000502:physiology; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014404:Tubulin / Q000378:metabolism
D000978:Antiparkinson Agents; D018492:Dopamine Antagonists; D026901:Membrane Transport Proteins; D039842:Neural Cell Adhesion Molecule L1; D014404:Tubulin; D004298:Dopamine