Molecular mechanism and gene therapy of familial ALS

家族性ALS的分子机制及基因治疗

• 批准号: 09470151
• 负责人: ABE Koji
• 金额: $ 3.58万
• 依托单位: Okayama University (1998-1999)Tohoku University (1997)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470151/
• 关键词: ALS; SOD; transgenic mice; gene therapy

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting predominantly motor neurons in the central nervous system. There has been no effective treatment, and the duration is usually 2-5 years. About 5-10% of ALS is thought to be familial (FALS) with an autosomal dominant inheritance, or less often recessive.We report here seven FALS families associated with four different missense mutations of the Cu/Zn SOD gene (D6F, H46R, L84V, A90V, I104F, S134N, and V148I), and each family has unique clinical characteristics. Protein tyrosin nitration of spinal motor neurons was found in ALS patients, but not in control subjects. With transgenic mice of G93A Cu/Zn SOD gene mutation, we found early and selective impairment of fast axonal transport by ligation of sciatic nerves. Furthermore, immunoreactivity of cell survival signal such as Akt and PI3K showed early decrease in spinal motor neurons, but immunoreactivities for cell death signals such as caspases or TUNEL was not positive until the advance stage of motor neuron death, indicating a critical imbalance of cell survival and death signals in dying motor neurons. In addition, -mediated Lace gene was effectively transferred and expressed in muscles and spinal motor neurons in transgenic symptomatic mice, and established a therapic basis for human ALS patients.

肌萎缩性侧索硬化症（ALS）是一种退化性疾病，影响中枢神经系统中主要是运动神经元。没有有效的治疗方法，持续时间通常为2 - 5年。大约5-10％的ALS被认为是具有常染色体显性遗传的家族性（fals）。我们在这里报告了与Cu/Zn Sod基因的四个不同错义突变相关的七个FALS家族（D6F，H46R，H46R，H46R，L84V，L84V，L84V，L84V，l84v，a90v，a90v，i104f，i104f，i104f，i104f，s134n和v14n和v148i和v148i and and and and and and and and and and and and and and and and and and。在ALS患者中发现脊柱运动神经元的蛋白酪氨酸硝化作用，但在对照组患者中未发现。使用G93A Cu/Zn SOD基因突变的转基因小鼠，我们发现了通过坐骨神经的连接来早期和选择性损害快速轴突转运。此外，诸如AKT和PI3K之类的细胞存活信号的免疫反应性表现出脊柱运动神经元的早期降低，但是直到运动神经元死亡的前进阶段，细胞死亡信号（例如caspase或tunel）的免疫反应性并不阳性，表明细胞生存和死亡信号的严重失效和死亡信号在染色体运动神经元中的生存信号严重。此外，在转基因症状小鼠的肌肉和脊柱运动神经元中有效地转移了介导的蕾丝基因，并为人类ALS患者建立了治疗基础。

项目成果

T. Hayashi, M. Sakurai, K. Abe, T. Sadahiro, H. Tabayashi, and Y. Itoyama: "Expression of angiogenic factors in rabbit spinal cord after transient ischaemia"Neuropathol. Appl. Neurobiol.. 25. 63-71 (1999)

T. Hayashi、M. Sakurai、K. Abe、T. Sadahiro、H. Tabayashi 和 Y. Itoyama：“短暂性缺血后兔脊髓中血管生成因子的表达”神经病理学。

Kitagawa et al.: "Adenovirus-mediated gene transfer of GONF prevents ischemic brain injury after transient MCA occlusion in rats"J. Cereb. Blood Flow Metabol.. 19. 1336-1344 (1999)

Kitakawa 等人：“腺病毒介导的 GONF 基因转移可预防大鼠短暂 MCA 闭塞后的缺血性脑损伤”J.

Ikeda et al.: "HSP70 and HSC70 mRNA induction in the brains, hearts, and livers of nonatal rats after hypoxic stress"Am. J. Obstet, Gynecol.. 180. 457-461 (1999)

Ikeda 等人：“缺氧应激后新生大鼠大脑、心脏和肝脏中 HSP70 和 HSC70 mRNA 的诱导”Am。

Abe et al.: "In vivo expression of adenoviral-mediated E-coli LacZ gene in igchemic and reper fused rat brain." Brain Res.763. 191-202 (1997)

Abe 等人：“腺病毒介导的大肠杆菌 LacZ 基因在免疫和再灌注融合大鼠脑中的体内表达。”

Abe et al.: "Neurons : necrotic vs apoptotic changes"Cerebral. Ischemia. 1. 217-232 (1999)

Abe 等人：“神经元：坏死与凋亡变化”大脑。