Dopamine depletion impairs precursor cell proliferation in Parkinson disease
Dopamine depletion impairs precursor cell proliferation in Parkinson disease
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DOI：
10.1038/nn1265
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发表时间：
2004-07-01
影响因子：
25
通讯作者：
Hirsch, EC
中科院分区：
文献类型：
--
作者：
Höglinger, GU;Rizk, P;Hirsch, EC
脑多巴胺缺乏是帕金森病的标志。由于多巴胺调节个体发生神经发生，多巴胺的耗竭可能会影响成年大脑室管膜下区和颗粒下区的神经前体。在这里，我们提供的超微结构证据表明，成人室管膜下区高增殖的前体细胞表达多巴胺受体并接受多巴胺能传入。实验中耗尽啮齿类动物的多巴胺降低了室管膜下区和颗粒下区的前体细胞的增殖。D2样受体(D2L)选择性激动剂可完全恢复细胞增殖。对成年室管膜下区神经前体进行的实验证实，D2L受体的激活直接增加了这些前体的增殖。帕金森病患者死后脑内室管膜下区的增殖细胞、颗粒下区和嗅球的神经前体细胞的数量一直减少。这些观察结果表明，帕金森病患者神经前体细胞的产生受到损害，这是多巴胺能神经丧失的结果。
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.