Tomac A, Widenfalk J, Lin L F, Kohno T, Ebendal T, Hoffer B J, Olson L
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8274-8. doi: 10.1073/pnas.92.18.8274.
The recently cloned, distant member of the transforming growth factor beta (TGF-beta) family, glial cell line-derived neurotrophic factor (GDNF), has potent trophic actions on fetal mesencephalic dopamine neurons. GDNF also has protective and restorative activity on adult mesencephalic dopaminergic neurons and potently protects motoneurons from axotomy-induced cell death. However, evidence for a role for endogenous GDNF as a target-derived trophic factor in adult midbrain dopaminergic circuits requires documentation of specific transport from the sites of synthesis in the target areas to the nerve cell bodies themselves. Here, we demonstrate that GDNF is retrogradely transported by mesencephalic dopamine neurons of the nigrostriatal pathway. The pattern of retrograde transport following intrastriatal injections indicates that there may be subpopulations of neurons that are GDNF responsive. Retrograde axonal transport of biologically active 125I-labeled GDNF was inhibited by an excess of unlabeled GDNF but not by an excess of cytochrome c. Specificity was further documented by demonstrating that another TGF-beta family member, TGF-beta 1, did not appear to affect retrograde transport. Retrograde transport was also demonstrated by immunohistochemistry by using intrastriatal injections of unlabeled GDNF. GDNF immunoreactivity was found specifically in dopamine nerve cell bodies of the substantia nigra pars compacta distributed in granules in the soma and proximal dendrites. Our data implicate a specific receptor-mediated uptake mechanism operating in the adult. Taken together, the present findings suggest that GDNF acts endogenously as a target-derived physiological survival/maintenance factor for dopaminergic neurons.
最近克隆出的转化生长因子β（TGF-β）家族的远亲成员——胶质细胞系源性神经营养因子（GDNF），对胎儿中脑多巴胺能神经元具有强大的营养作用。GDNF对成年中脑多巴胺能神经元也具有保护和修复活性，并且能有效保护运动神经元免受轴突切断诱导的细胞死亡。然而，要证明内源性GDNF在成年中脑多巴胺能回路中作为靶源性营养因子发挥作用，需要有证据表明其能从靶区域的合成部位特异性转运至神经细胞体本身。在此，我们证明GDNF可被黑质纹状体通路的中脑多巴胺能神经元逆行转运。纹状体内注射后逆行转运的模式表明，可能存在对GDNF有反应的神经元亚群。生物活性125I标记的GDNF的逆行轴突运输被过量的未标记GDNF抑制，但未被过量的细胞色素c抑制。通过证明另一个TGF-β家族成员TGF-β1似乎不影响逆行运输，进一步证实了特异性。通过纹状体内注射未标记的GDNF进行免疫组织化学也证明了逆行运输。在黑质致密部的多巴胺神经细胞体中特异性发现了GDNF免疫反应性，其以颗粒形式分布于胞体和近端树突中。我们的数据表明在成年个体中存在一种特定的受体介导的摄取机制。综上所述，目前的研究结果表明，GDNF作为一种内源性的靶源性生理存活/维持因子，对多巴胺能神经元发挥作用。
