GDNF as a therapeutic regend for human muscle diseases

多种神经营养因子已被证实可促进运动神经元的存活。胶质细胞系来源的神经营养因子（GDNF）作为靶源性营养因子之一，通过GDNF受体α-1 （GFRα-1）和c-Ret等受体复合物对运动神经元发挥作用。c-Ret受体酪氨酸激酶是GDNF配体家族的重要组成部分，该配体家族由胶质细胞系来源的神经营养因子、神经蛋白、persephin和artemin组成。虽然c-Ret本身不能结合GDNF，但它在与GFRα-1 （GDNF受体α-1）复合物中转导信号，GFRα-1是一种高亲和力结合GDNF的糖基磷脂酰肌醇（GPI）锚定蛋白。因此，配体结合和跨膜信号分别被认为是GFRα-1和c-Ret所指定的。面神经切开术诱导成年大鼠GFRα-1和c-Ret mrna上调。在肛肠切开术部位局部给药GDNF导致GFRα-1 mRNA上调，而c-Ret未上调。该结果提示GFRα-1和c-Ret上调GDNF受体的机制可能存在差异。

A variety of neurotrophic factors have been characterized for promoting motor neuron survival. As one of the target-derived trophic factors, glial cell line-derived neurotrophic factor (GDNF) has been shown to exert its effects on motor neurons via a receptor complex including GDNF receptor alpha 1 (GFRα-1) and c-Ret. The c-Ret receptor tyrosine kinase is an essential component of the GDNF ligand family that consists of glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin. Although c-Ret cannot bind GDNF by itself, it transduces signaling in a complex with GFRα-1 (GDNF receptor alpha-1), a glycosyl phosphatidylinositol (GPI)-anchored protein that binds GDNF with high affinity. Thus, the ligand binding and transmembrane signaling are regarded to be specified for GFRα-1 and c-Ret, respectively. Axotomy of facial nerve induced up-regulation of GFRα-1 and c-Ret mRNAs in adult rats. The local administration of GDNF at the site of axotomy resotred up-regulation of GFRα-1 mRNA but not c-Ret. This result indicates that the mechanism of GDNF receptor up-regulation may differ between GFRα-1 and c-Ret.