Detailed characterization of Humanin, a newly identified anti-Alzheimer's disease peptide and potential starting point for development of the first curative therapy for Alzheimer's disease

到目前为止，还没有开发出针对阿尔茨海默病（AD）的基本疗法。Humanin是一种新发现的抑制阿尔茨海默病（AD）相关损伤引起的细胞死亡的肽。我们研究了HN肽神经保护功能的结构/功能关系。当全长HN中的Pro 3、Ser 7、Cys 8、Leu 9、Leu 12、Thr 13、Ser 14或Pro 19变为Ala时，HN衍生物失去其神经保护活性。Pro3-Pro 19是HN神经保护作用的核心结构域。HN形成同源二聚体，这是HN神经保护所必需的，并且Ala取代Ser 7或Leu 9使HN的同源二聚化无效。HN应该是分泌的，并且能够从外部起作用，这表明某种细胞表面受体是HN的靶点。HN免疫反应性在AD脑枕叶中的一些完整的大神经元中检测到，但在其他脑区域或年龄匹配的对照脑中未检测到。在小鼠中，3 kDa免疫反应性肽 ...更多信息 已在3周龄小鼠的睾丸和结肠中检测到HN的推断分子量ide。这种免疫反应性在12周龄小鼠的结肠中消失，表明HN产生的年龄依赖性调节。我们确定TRIM 11作为HN相互作用蛋白，一个成员的蛋白质家族包含一个三重基序（TRIM）。TRIM 11由RING指结构域组成，其是推定的E3泛素连接酶。值得注意的是，TRIM 11在细胞内泛素化并降解HN。我们还发现，通过Gly取代Ser 14增强HN神经保护功能是通过D-Ser异构化特异性模仿的。因此，可以想象HN肽从HN基因转录和翻译，然后通过Ser 14处的翻译后修饰，即D-Ser 14异构化，转化为最大活性形式。考虑到胰岛素样生长因子结合蛋白3是血液中的HN结合蛋白[20]，HN主要在中枢神经系统（CNS）外的组织中产生，通过结合结合蛋白转移，并在穿过血脑屏障时进一步活化，并递送至CNS神经元，这是一个有吸引力的假设。考虑到其对AD相关损伤的广泛特异性拯救活性，HN是一种有希望的AD治疗种子，旨在完全抑制神经元损失。少

No fundamental therapy for Alzheimer's disease (AD) has so far been developed. Humanin is a newly identified peptide that suppresses cell death by Alzheimer's disease (AD)-related insults. We have investigated the structure/function relationship for the neuroprotective function of HN peptide. When either Pro3, Ser7, Cys8, Leu9, Leu 12, Thr13, Ser14, or Pro19 is changed to Ala in full-length HN, the HN derivatives lose its neuroprotective activity. Pro3-Pro19 turned out to be the core domain for neuroprotection by HN. HN forms a homodimer, which is essential for HN neuroprotection, and that Ala substitution for Ser7 or Leu9 nullifies homodimerization by HN. HN should be secreted and be able to act from the outside, indicating that a certain cell-surface receptor is the target of HN. HN immunoreactivity is detected in some of the intact large neurons in the occipital lobe of an AD brain, but not in other brain regions or in an age-matched control brain. In mice, 3 kDa immunoreactive pept … More ide, the deduced molecular weight of HN, has been detected in the testes and colons of 3-week-old mice. This immunoreactivity disappears in the colon of 12-week-old mice, pointing to the age-dependent regulation of HN production. We identified TRIM11 as a HN-interacting protein, a member of a protein family containing a tripartite motif (TRIM). TRIM11 is composed of a RING finger domain, which is a putative E3 ubiquitin ligase. Notably, TRIM11 ubiquitinizes and degrades HN intracellularly. We also found that the potentiation of HN neuroprotective function by Gly substitution for Ser14 is specifically mimicked by D-Ser isomerization. Therefore, it is conceivable that HN peptide is transcribed and translated from the HN gene and then converted to the maximally active form by posttranslational modification at Ser14, that is, D-Ser14 isomerization. Considering that insulin-like growth factor-binding protein 3 is an HN-binding protein in the blood [20], it is an attractive hypothesis that HN is mainly produced in tissues outside the central nervous system (CNS), transferred by binding to the binding protein, and further activated as it passes through the blood-brain barrier, and is delivered to CNS neurons. Considering the broad specificity of its rescue activity to AD-relevant insults, HN is a promising seed for AD therapy aiming the complete suppression of neuronal loss. Less