Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide
Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide
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DOI：
10.1046/j.1471-4159.1999.0721283.x
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发表时间：
1999-03-01
影响因子：
4.7
通讯作者：
Gozes, I
中科院分区：
文献类型：
--
作者：
Bassan, M;Zamostiano, R;Gozes, I
神经元的脆弱性和损失的不可逆性使得神经保护化合物的发现具有根本的重要性。在这里，一种新的蛋白质（828个氨基酸，p15.99），来自小鼠神经胶质细胞的完整编码序列，被揭示。该序列包含（1）神经保护肽NAPVSIPQ，与先前报道的活性依赖性神经营养因子具有结构和免疫同源性;（2）谷氧还蛋白活性位点;（3）锌结合结构域。基因表达在小鼠海马和小脑中富集，并且在神经肽血管活性肠肽的存在下在大脑皮质星形胶质细胞中增强。在混合的神经元-星形胶质细胞培养物中，NAPVSIPQ在亚飞摩尔浓度下提供神经保护，对抗与河豚毒素（电阻断）、β-淀粉样肽（阿尔茨海默病神经毒素）、N-甲基-D-天冬氨酸（兴奋性毒性）和人类免疫缺陷病毒包膜蛋白相关的毒性。每天给新生的载脂蛋白E缺陷小鼠注射NAPVSIPQ，可以加速发育反射的获得，并防止短期记忆缺陷。比较研究表明，在载脂蛋白E缺乏模型中，NAPVSIPQ比其他神经保护肽更有效。建议以NAPVSIPQ作为先导化合物进行合理的抗神经变性药物设计的潜在基础。新的mRNA转录物在大脑中的相对富集和血管活性肠肽（一种已建立的神经保护物质）存在下的增加，意味着克隆蛋白在神经元功能中的作用。
The vulnerability of neurons and the irreversibility of loss make discoveries of neuroprotective compounds fundamentally important. Here, the complete coding sequence of a novel protein (828 amino acids, pl 5.99), derived from mouse neuroglial cells, is revealed. The sequence contained (1) a neuroprotective peptide, NAPVSIPQ, sharing structural and immunological homologies with the previously reported, activity-dependent neurotrophic factor; (2) a glutaredoxin active site; and (3) a zinc binding domain. Gene expression was enriched in the mouse hippocampus and cerebellum and augmented in the presence of the neuropeptide vasoactive intestinal peptide, in cerebral cortical astrocytes. In mixed neuron-astrocyte cultures, NAPVSIPQ provided neuroprotection at subfemtomolar concentrations against toxicity associated with tetrodotoxin (electrical blockade), the p-amyloid peptide (the Alzheimer's disease neurotoxin), N-methyl-D-aspartate (excitotoxicity), and the human immunodeficiency virus envelope protein. Daily NAPVSIPQ injections to newborn apolipoprotein E-deficient mice accelerated the acquisition of developmental reflexes and prevented short-term memory deficits. Comparative studies suggested that NAPVSIPQ was more efficacious than other neuroprotective peptides in the apolipoprotein E-deficiency model. A potential basis for rational drug design against neurodegeneration is suggested with NAPVSIPQ as a lead compound. The relative enrichment of the novel mRNA transcripts in the brain and the increases found in the presence of vasoactive intestinal peptide, an established neuroprotective substance, imply a role for the cloned protein in neuronal function.