5月26日《細胞生物學雜志》（Journal of Cell Biology）刊載了一項最新 研究成果，科學家近日利用遺傳手段改造一種病毒，成功制備出一種針對亨 廷頓蛋白的內抗體（intrabody），它能夠“吞噬”在亨廷頓氏病中導致神經 退化的變異亨廷頓蛋白質塊。實驗表明，這種內抗體能夠改善患有亨廷頓氏 病小鼠的四肢活動能力。研究人員表示，雖然目前尚無法在人類身上應用， 但或許可以根據此內抗體的結構信息開發出藥物模擬它的效果。 在亨廷頓氏病中，編碼亨廷頓蛋白的基因的一部分會變異性增長，它重復復 制了三個堿基CAG（谷氨酸的編碼子）幾十次。變異的蛋白某一區域也出現了 谷氨酸的重復序列，稱為多聚谷氨酸，它會使變異蛋白在腦細胞中叢生。 研究顯示，產生內抗體和變異亨廷頓蛋白的細胞能夠更快地去除變異蛋白， 產生的亨廷頓蛋白塊也較少。亨廷頓氏病小鼠模型表明，這種內抗體雖然沒 有延長它們的壽命，但卻改善了它們四肢的活動能力。 研究人員表示這是首次在活小鼠體內進行內抗體效用的研究。這一抗體也將 有助于研究其它神經退行性疾病，如阿爾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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