Koeberle P D, Bähr M
Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
Cell Death Differ. 2008 Mar;15(3):471-83. doi: 10.1038/sj.cdd.4402281. Epub 2007 Dec 7.
Glial cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) protect retinal ganglion cells (RGCs) from axotomy-induced apoptosis. It is likely that neuroprotection by GDNF or NTN in the adult central nervous system (CNS) involves indirect mechanisms and independent signal transduction events. Extracellular glutamate is a trigger of apoptosis in injured RGCs, and glutamate transporter levels can be upregulated by GDNF. Therefore, GDNF may indirectly protect RGCs by enhancing glutamate uptake in the retina. We studied the upregulation of the glutamate transporters GLAST-1 and GLT-1 by GDNF and NTN, and the intracellular pathways required for GDNF/NTN neuroprotection. GDNF required phosphoinositide-3 kinase (PI3K) and Src activity to upregulate GLAST-1 and GLT-1. NTN required PI3K activity to upregulate GLAST-1 and did not affect GLT-1 levels. PI3K activity was also important for GDNF and NTN neuroprotection following optic nerve transection. However, GDNF also required Src and mitogen-activated protein kinase activity to prevent RGC apoptosis. RNA interference demonstrated that the upregulation of GLAST-1 by GDNF and NTN is required to rescue RGCs. Thus, additional independent signal transduction events, together with the upregulation of GLT-1 by GDNF, differentiate the biological activity of GDNF from NTN. Furthermore, the upregulation of the glial glutamate transporter GLAST-1 by both factors is an indirect neuroprotective mechanism in the CNS.
胶质细胞源性神经营养因子（GDNF）和神经营养素（NTN）可保护视网膜神经节细胞（RGCs）免受轴突切断诱导的凋亡。GDNF或NTN在成体中枢神经系统（CNS）中的神经保护作用可能涉及间接机制和独立的信号转导事件。细胞外谷氨酸是受损RGCs凋亡的触发因素，GDNF可上调谷氨酸转运体水平。因此，GDNF可能通过增强视网膜中的谷氨酸摄取间接保护RGCs。我们研究了GDNF和NTN对谷氨酸转运体GLAST-1和GLT-1的上调作用，以及GDNF/NTN神经保护所需的细胞内信号通路。GDNF上调GLAST-1和GLT-1需要磷酸肌醇-3激酶（PI3K）和Src活性。NTN上调GLAST-1需要PI3K活性，且不影响GLT-1水平。PI3K活性对视神经切断后的GDNF和NTN神经保护也很重要。然而GDNF还需要Src和丝裂原活化蛋白激酶活性来防止RGC凋亡。RNA干扰表明，GDNF和NTN上调GLAST-1对挽救RGCs是必需的。因此，额外的独立信号转导事件，以及GDNF对GLT-1的上调，区分了GDNF与NTN的生物学活性。此外，两种因子对胶质谷氨酸转运体GLAST-1的上调是CNS中的一种间接神经保护机制。
