Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides
Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides
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DOI：
10.1073/pnas.94.9.4778
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发表时间：
1997-04-29
影响因子：
11.1
通讯作者：
OBrien, JS
中科院分区：
文献类型：
--
作者：
Hiraiwa, M;Taylor, EM;OBrien, JS
鞘脂激活蛋白原（Prosaposin）是鞘脂激活蛋白A、B、C和D的前体，最近被鉴定为神经营养因子。在四种成熟鞘脂激活蛋白中，仅发现鞘脂激活蛋白C增加这些细胞类型中的硫苷脂浓度，通过使用包含位于鞘脂激活蛋白C结构域中的神经营养序列的肽（前肽）获得了类似的结果。剂量-反应曲线证明了鞘脂激活蛋白C和前肽在低纳摩尔浓度（5-10 nM）下的最大增强。在CG 4少突胶质细胞中，14聚体前肽TX 14（A）引起的硫苷脂浓度的增加比原代雪旺细胞中的高约3倍。一个突变的前肽与一个单一的氨基酸取代的Asn -> Asp是无活性的。Prosaptides不诱导原代雪旺细胞、iSC细胞或CG 4少突胶质细胞的细胞增殖，但纳摩尔浓度的prosaptides防止iSC细胞和CG 4少突胶质细胞的细胞死亡。免疫印迹分析表明，在用1-5 nM浓度的prosaptides处理5分钟后，促分裂原活化蛋白激酶p-42和p-44亚型的磷酸化增强3- 5倍。这些研究结果表明，saposin和prosaptides结合到一个受体，启动信号转导，以促进meylin脂质合成和延长细胞存活的雪旺细胞和少突胶质细胞。在有髓鞘神经的发育和修复过程中，鞘脂激活蛋白原可能在体内起着髓鞘营养因子的作用，这解释了在鞘脂激活蛋白原缺陷的小鼠和人类中观察到的髓鞘缺乏。
Prosaposin, the precursor of saposins A, B, C, and D, was recently identified as a neurotrophic factor, Herein prosaposin was found to increase sulfatide concentrations in primary and transformed Schwann cells (iSC) and oligodendrocytes (differentiated CG4 cells), Of the four mature saposins, only saposin C was found to increase sulfatide concentrations in these cell types, A similar result was obtained by using peptides (prosaptides) encompassing the neurotrophic sequence located in the saposin C domain, Dose-response curves demonstrated maximal enhancement by saposin C and prosaptides at low nanomolar concentrations (5-10 nM). The increase in sulfatide concentration by a 14-mer prosaptide, TX14(A), in CG4 oligodendrocytes was about 3-fold greater than in primary Schwann cells. A mutant prosaptide with a single amino acid replacement of Asn --> Asp was inactive. Prosaptides did not induce cell proliferation of primary Schwann cells, iSC cells, or CG4 oligodendrocytes but nanomolar concentrations of prosaptides prevented cell death of iSC cells and CG4 oligodendrocytes. Immunoblot analysis demonstrated that phosphorylation of both mitogen-activated protein kinase p-42 and p-44 isoforms were enhanced 3- to 5-fold after 5 min of treatment with prosaptides at concentrations of 1-5 nM. These findings suggest that prosaposin and prosaptides bind to a receptor that initiates signal transduction to promote meylin lipid synthesis and prolong cell survival in both Schwann cells and oligodendrocytes. Prosaposin may function as a myelinotrophic factor in vivo during development and repair of myelinated nerves explaining the deficiency of myelin observed in prosaposin-deficient mice and humans.