Analyses for the function and related gene of humanin that suppresses cell death induced by mutant Alzheimer disease genes

人蛋白(FIN)是一种由24个氨基酸组成的多肽，可保护细胞免受阿尔茨海默病(AD)基因突变诱导的细胞凋亡，但其对其他细胞毒因子的保护作用尚不清楚。该项目的目的是确定HN对AD以外的各种疾病或细胞死亡的治疗潜力。采用去血清诱导大鼠嗜铬细胞瘤PC12细胞凋亡的方法，检测其对非特异性神经细胞死亡的影响。HN通过抑制caspase 3活性，显著减少细胞死亡和核DNA片段化。为了进一步扩展FIN的适用性，我们研究了在无血清条件下培养的人淋巴细胞。FIN可提高ATP水平，抑制细胞死亡，提示FIN可用于治疗ATP缺乏的疾病，如帕金森病和线粒体疾病(MDS)。因此，我们测试了FIN在线粒体脑病、乳酸酸中毒和卒中样…中的作用更多情节(MELAS)，最常见的MD之一。MELAS患者的外周血淋巴细胞在无血清条件下培养，与对照组相比，MELAS细胞中的ATP水平显著降低。FIN可提高细胞内ATP水平，抑制细胞死亡和线粒体DNA拷贝数。在人神经母细胞瘤SK-N-MC细胞和横纹肌肉瘤TE671细胞中也观察到了类似的细胞保护和产生ATP的作用，这表明FIN可以减轻脑和肌肉的损伤，这是MELAS的主要组织，因为对ATP的需求很高。细胞凋亡可能是一种防御机制，可以清除线粒体异常增加的细胞，以应对ATP缺乏和活性氧的形成，但它可能会干扰细胞功能，导致MELAS进一步的组织损伤。HN打破了这一恶性循环，因此，它是一种有前途的MDS治疗候选药物。总之，我们为HN更广泛的治疗范围提供了实验证据。较少

Humanin (FIN) is a 24-amino-acid peptide that protects cells from apoptosis induced by mutant Alzheimer's disease (AD) genes, but its protective effect against other cytotoxic factors remains unclear. The aim of this project is to establish the therapeutic potential of HN for various diseases or types of cell death other than AD. The effect on non-specific neuronal cell death was tested using rat pheochromocytoma PC12 cells undergoing apoptosis after serum deprivation. HN significantly decreased cell death and fragmentation of nuclear DNA with the suppression of caspase 3 activity. To further extend the applicability of FIN, we examined human lymphocytes cultured under serum-deprived condition. FIN increased ATP level and suppressed cell death, suggesting that this peptide may be used for the treatment of disorders with ATP deficiency, such as Parkinsons disease and mitochondrial diseases (MDs). Therefore, we tested FIN in mitochondrial encephalopathy, lactic acidosis, and stroke-like … More episodes (MELAS), one of the most common MDs. Readily obtainable peripheral lymphocytes from patients with MELAS were cultured under serum-deprived condition, which significantly decreased the ATP levels in MELAS cells compared with those in controls. FIN increased the ATP levels, and suppressed cell death and mitochondrial DNA copy number. Similar cytoprotective and ATP-producing effects were observed in human neuroblastoma SK-N-MC cells and rhabdomyosarcoma TE671 cells, suggesting that FIN may alleviate the impairment in brain and muscle, which are the tissues predominantly involved in MELAS because of high ATP demand. Apoptosis may be a defense mechanism to remove cells with increased abnormal mitochondria in response to ATP deficiency and formation of reactive oxygen species, however, it may disturb cellular function, leading to further tissue damages in MELAS. HN breaks this vicious circle, and therefore, it is a promising therapeutic candidate for MDs. In conclusion, we have provided experimental evidence for the broader therapeutic spectrum of HN. Less