Chronic deprivation of TrkB signaling leads to selective late-onset nigrostriatal dopaminergic degeneration.
Chronic deprivation of TrkB signaling leads to selective late-onset nigrostriatal dopaminergic degeneration.
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DOI：
10.1016/j.expneurol.2010.12.018
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发表时间：
2011-03
影响因子：
5.3
通讯作者：
Xu, Baoji
中科院分区：
文献类型：
--
作者：
Baydyuk, Maryna;Nguyen, Madeline T.;Xu, Baoji
关键词：
帕金森病（PD）的病理标志是黑质腹侧部（SNc）多巴胺能（DA）神经元的选择性和进行性丢失。在绝大多数情况下，PD的表现是散发性的，其病因仍然未知。几项尸检研究表明PD患者SNc中脑源性神经营养因子（BDNF）水平降低。应用BDNF促进PD动物模型中DA能神经元的存活。在这里，我们表明，BDNF信号通过其TrkB受体酪氨酸激酶是重要的黑质纹状体DA神经元在老化的大脑中的生存。免疫组化显示TrkB受体表达于黑质腹侧被盖区（VTA）和黑质腹侧被盖区（SNc）的DA能神经元。然而，在12-24月龄时，仅在SNc中发生DA神经元的显著损失，而在TrkB亚型小鼠的VTA中没有，其中TrkB受体的表达量为正常量的四分之一到三分之一。神经元的损失伴随着纹状体多巴胺能轴突终末的减少，以及SNc和纹状体的神经胶质增生。此外，TrkB突变小鼠的黑质纹状体DA神经元对神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）过敏，MPTP是一种选择性杀死DA神经元的线粒体复合物I抑制剂。这些结果表明，BDNF到TrkB信号在黑质纹状体系统的长期维持中起着重要作用，其缺陷可能有助于PD的进展。
The pathological hallmark of Parkinson's disease (PD) is a selective and progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). In the vast majority of cases the appearance of PD is sporadic, and its etiology remains unknown. Several postmortem studies demonstrate reduced levels of brain-derived neurotrophic factor (BDNF) in the SNc of PD patients. Application of BDNF promotes the survival of DA neurons in PD animal models. Here we show that BDNF signaling via its TrkB receptor tyrosine kinase is important for survival of nigrostriatal DA neurons in aging brains. Immunohistochemistry revealed that the TrkB receptor was expressed in DA neurons located in the SNc and ventral tegmental area (VTA). However, a significant loss of DA neurons occurred at 12-24 months of age only in the SNc but not in the VTA of TrkB hypomorphic mice in which the TrkB receptor was expressed at a quarter to a third of the normal amount. The neuronal loss was accompanied by a decrease in dopaminergic axonal terminals in the striatum and by gliosis in both the SNc and striatum. Furthermore, nigrostriatal DA neurons in the TrkB mutant mice were hypersensitive to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor that selectively kills DA neurons. These results suggest that BDNF-to-TrkB signaling plays an important role in the long-term maintenance of the nigrostriatal system and that its deficiency may contribute to the progression of PD.
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影响因子：
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作者：
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通讯作者：
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作者：
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