5月26日《细胞生物学杂志》（Journal of Cell Biology）刊载了一项最新 研究成果，科学家近日利用遗传手段改造一种病毒，成功制备出一种针对亨 廷顿蛋白的内抗体（intrabody），它能够“吞噬”在亨廷顿氏病中导致神经 退化的变异亨廷顿蛋白质块。实验表明，这种内抗体能够改善患有亨廷顿氏 病小鼠的四肢活动能力。研究人员表示，虽然目前尚无法在人类身上应用， 但或许可以根据此内抗体的结构信息开发出药物模拟它的效果。 在亨廷顿氏病中，编码亨廷顿蛋白的基因的一部分会变异性增长，它重复复 制了三个碱基CAG（谷氨酸的编码子）几十次。变异的蛋白某一区域也出现了 谷氨酸的重复序列，称为多聚谷氨酸，它会使变异蛋白在脑细胞中丛生。 研究显示，产生内抗体和变异亨廷顿蛋白的细胞能够更快地去除变异蛋白， 产生的亨廷顿蛋白块也较少。亨廷顿氏病小鼠模型表明，这种内抗体虽然没 有延长它们的寿命，但却改善了它们四肢的活动能力。 研究人员表示这是首次在活小鼠体内进行内抗体效用的研究。这一抗体也将 有助于研究其它神经退行性疾病，如阿尔茨海默氏症或克雅氏病。 Journal of Cell Biology Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin abstract> Mutant huntingtin accumulates in the neuronal nuclei and processes, which suggests that its subcellular localization is critical for the pathology of Huntington's disease (HD). However, the contribution of cytoplasmic mutant huntingtin and its aggregates in neuronal processes (neuropil aggregates) has not been rigorously explored. We generated an intracellular antibody (intrabody) whose binding to a unique epitope of human huntingtin is enhanced by polyglutamine expansion. This intrabody decreases the cytotoxicity of mutant huntingtin and its distribution in neuronal processes. When expressed in the striatum of HD mice via adenoviral infection, the intrabody reduces neuropil aggregate formation and ameliorates neurological symptoms. Interaction of the intrabody with mutant huntingtin increases the ubiquitination of cytoplasmic huntingtin and its degradation. These findings suggest that the intrabody reduces the specific neurotoxicity of cytoplasmic mutant huntingtin and its associated neurological symptoms by preventing the accumulation of mutant huntingtin in neuronal processes and promoting its clearance in the cytoplasm. --

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