Kittappa Raja, Chang Wendy W, Awatramani Rajeshwar B, McKay Ronald D G
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Biol. 2007 Dec;5(12):e325. doi: 10.1371/journal.pbio.0050325.
Parkinson disease affects more than 1% of the population over 60 y old. The dominant models for Parkinson disease are based on the use of chemical toxins to kill dopamine neurons, but do not address the risk factors that normally increase with age. Forkhead transcription factors are critical regulators of survival and longevity. The forkhead transcription factor, foxa2, is specifically expressed in adult dopamine neurons and their precursors in the medial floor plate. Gain- and loss-of-function experiments show this gene, foxa2, is required to generate dopamine neurons during fetal development and from embryonic stem cells. Mice carrying only one copy of the foxa2 gene show abnormalities in motor behavior in old age and an associated progressive loss of dopamine neurons. Manipulating forkhead function may regulate both the birth of dopamine neurons and their spontaneous death, two major goals of regenerative medicine.
帕金森病影响超过1%的60岁以上人群。帕金森病的主要模型基于使用化学毒素杀死多巴胺能神经元，但未涉及通常随年龄增长而增加的风险因素。叉头转录因子是生存和长寿的关键调节因子。叉头转录因子foxa2在成年多巴胺能神经元及其内侧底板的前体中特异性表达。功能获得和功能丧失实验表明，该基因foxa2在胎儿发育期间以及从胚胎干细胞生成多巴胺能神经元时是必需的。仅携带一个foxa2基因拷贝的小鼠在老年时表现出运动行为异常以及多巴胺能神经元的相关渐进性丧失。操纵叉头功能可能会调节多巴胺能神经元的生成及其自然死亡，这是再生医学的两个主要目标。
