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

护脑素抑制阿尔茨海默病突变基因诱导的细胞死亡的功能及相关基因分析

• 批准号: 14570612
• 负责人: UENO Satoshi
• 金额: $ 1.86万
• 依托单位: Nara Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570612/
• 关键词: Humanin; apoptosis; mitochondrial disease; ミトコンドリア病; ヒューマン; 神経細胞死

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

Humanin（FIN）是一种由24个氨基酸组成的肽，可保护细胞免受突变型阿尔茨海默病（AD）基因诱导的凋亡，但其对其他细胞毒性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类型的治疗潜力。使用血清剥夺后经历凋亡的大鼠嗜铬细胞瘤PC 12细胞测试对非特异性神经元细胞死亡的影响。HN能显著降低细胞死亡率和核DNA断裂率，并抑制caspase 3活性。为了进一步扩展FIN的适用性，我们研究了在血清剥夺条件下培养的人淋巴细胞。FIN增加ATP水平并抑制细胞死亡，表明这种肽可用于治疗ATP缺乏症，如帕金森病和线粒体疾病（MD）。因此，我们在线粒体脑病、乳酸性酸中毒和中风样 ...更多信息 MELAS（MELAS）是最常见的MD之一。将MELAS患者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ATP水平显著降低。FIN增加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TE 671细胞中观察到类似的细胞保护和ATP产生作用，表明FIN可以减轻脑和肌肉的损伤，这是由于高ATP需求而主要参与MELAS的组织。细胞凋亡可能是一种防御机制，以消除细胞异常线粒体增加，以应对ATP缺乏和活性氧的形成，但它可能会干扰细胞功能，导致进一步的组织损伤在MELAS。HN打破了这种恶性循环，因此，它是一个有前途的治疗MDs的候选药物。总之，我们为HN的更广泛的治疗谱提供了实验证据。少

项目成果

Kariya S: "Humanin may provide therapeutic tool for mitochondria-related diseases by accelerating transcription activity of mitochondria DNA"Ann Neurol. 52. S89 (2002)

Kariya S：“Humanin 可能通过加速线粒体 DNA 的转录活性，为线粒体相关疾病提供治疗工具”Ann Neurol。

仮屋眞吾: "Humanin inhibits cell death of serum-deprived PC12h cells."Neuroreport. 13. 903-907 (2002)

Shingo Kariya：“Humanin 抑制血清剥夺的 PC12h 细胞的细胞死亡。”Neuroreport。13. 903-907 (2002)

仮屋眞吾: "Humanin improves bioenergetic state of cells harboring A3243G mitochondrial DNA mutation."Ann Neurol. 54. S46 (2003)

Shingo Kariya：“人素改善含有 A3243G 线粒体 DNA 突变的细胞的生物能状态。”Ann Neurol 54. S46 (2003)

Kariya S: "Humanin Improves impaired metabolic activity and prolongs survival of serum-deprived human lymphocytes"Mol Cell Biochem. 254. 83-89 (2003)

Kariya S：“Humanin 改善受损的代谢活动并延长血清剥夺的人淋巴细胞的存活时间”Mol Cell Biochem。

Shingo Kariya: "Humanin improves impaired metabolic activity and prolongs survival of serum-deprived human lymphocytes"Molecular and Cellular Biochemistry. 254・1-2. 83-89 (2003)

Shingo Kariya：“人素改善受损的代谢活性并延长血清剥夺的人淋巴细胞的存活”《分子和细胞生物化学》254・1-89（2003）。