Mechanism of neurotrophin processing which determines survival or death of neurons

神经营养因子，包括NGF和BDNF，不仅作为成熟形式分泌，而且作为前体分泌。两种形式的神经营养因子对神经元的作用相反，即存活或死亡。因此，从前体到成熟神经营养因子的加工步骤是极其重要的。对以下几点进行了考察。1、明确了决定加工效率的神经营养因子分子内序列。它们的前区c端对它们的加工特别有效。影响神经营养因子加工的细胞内蛋白现在正在与proNGF相互作用的基础上进行筛选。3、高密度细胞刺激了成熟神经营养因子的产生，但细胞外的前体细胞向成熟神经营养因子的变化可以忽略不计。目前正在研究高密度细胞中加工酶的表达。4、为了构建敏感的proNGF的EIA检测系统，利用DNA重组技术在昆虫细胞中产生了不可切割的proNGF，其抗体正在制备中。由于前神经营养因子的产生被认为与神经退行性疾病有关，因此这种敏感的EIA分析系统应该是有用的。研究发现，NGF前区低聚糖对NGF的加工和分泌至关重要。目前正在研究前肽中寡糖的位置对细胞中proongf糖型的加工和代谢的影响。当NGF及其受体在细胞中共表达时，细胞有死亡倾向。这表明细胞内发生了NGF及其受体的相互作用，其机制目前正在研究中。

Neurotrophins, including NGF and BDNF, are secreted not only as mature forms but also as precursors. The two forms of neurotrophins exhibit opposite effects on neurons, namely survival or death. Therefore, the processing step from precursor to mature neurotrophin is extremely important. Following points have been examined.1, Intramolecular sequence of neurotrophins that determined the processing efficiency was clarified. The C-terminal side of their pro-region was especially effective on their processing.2, Intracellular proteins that affect the neurotrophin processing are now being screened on the basis of the interaction with proNGF.3, The high density of cells stimulated partially the production of mature NGF, although the extracellular change of precursor to mature neurotrophin was negligible with the cultured cells. The expression of processing enzymes by high density cells is now being examined.4, In order to construct sensitive EIA assay system of proNGF, uncleavable proNGF was produced by DNA recombinant technique in the insect cells, and its antibody is now being made. Such a sensitive EIA assay system should be useful since the production of pro-neurotrophins is considered to be linked to neurodegenerative diseases.5, Oligosaccharides in the pro-region of NGF was found to be essential for the processing and secretion of NGF. The effect of the oligosaccharide location in propeptides on the processing and the metabolism of the aglyco-form of proNGF in cells is now being examined.6, When NGF and its receptors were co-expressed in cells, the cells had a tendency to die. This suggests the intracellular interaction of NGF and its receptors occurred, which mechanism is now being examined.