亨廷顿舞蹈症（Huntington Disease, HD），又称大舞蹈病，是一种常染色体显性遗传的神经退行性疾病，在欧美人群中，平均每十万人中有5至10人罹患此病。HD病人的主要症状包括运动、认知功能及情感障碍。此病一般在中年人群中发病最终导致死亡。亨廷顿舞蹈症发病的主要原因是患者第四号染色体上的亨廷顿基因（Huntingtin gene，HTT）的CAG 重复序列超过36个，造成亨廷顿蛋白构象异常并在脑内高度聚集及导致神经细胞死亡。科学家们正试图采用各种方法降低亨廷顿蛋白的表达水平而达到治疗HD的效果。然而由于亨廷顿蛋白对于小鼠胚胎早期发育至关重要，如何有效及安全地减少亨廷顿蛋白的表达仍为当前治疗HD的一大难题。

中国科学院遗传与发育生物学研究所李晓江研究组一直致力于研究包括帕金森综合症、亨廷顿舞蹈症在内的神经退行性疾病的致病机理。通过基因敲入的方法，他们利用人源亨廷顿突变蛋白氨基端片段取代小鼠内源性亨廷顿蛋白制备了亨廷顿基因敲入小鼠。研究发现仅靠氨基端片段的亨廷顿蛋白不足以保证小鼠的胚胎发育但可以造成亨廷顿舞蹈症的表型。而缺失氨基端片段的亨廷顿蛋白对神经元的发育分化是必需的。该研究首次提出了通过去除亨廷顿突变蛋白氨基端可有效地治疗HD的设想，为治疗HD提供了新的思路。

该研究结果于5月20日在线发表于pLOS Genetics。李晓江研究组的博士研究生刘旭东为该论文的第一作者。该研究得到基金委重大研究计划及分子发育生物学国家重点实验室的资助。

原文摘要：

N-terminal Huntingtin Knock-In Mice: Implications of Removing the N-terminal Region of Huntingtin for Therapy

The Huntington’s disease (HD) protein, huntingtin (HTT), is a large protein consisting of 3144 amino acids and has conserved N-terminal sequences that are followed by a polyglutamine (polyQ) repeat. Loss of Htt is known to cause embryonic lethality in mice, whereas polyQ expansion leads to adult neuronal degeneration. Whether N-terminal HTT is essential for neuronal development or contributes only to late-onset neurodegeneration remains unknown. We established HTT knock-in mice (N160Q-KI) expressing the first 208 amino acids of HTT with 160Q, and they show age-dependent HTT aggregates in the brain and neurological phenotypes. Importantly, the N-terminal mutant HTT also preferentially accumulates in the striatum, the brain region most affected in HD, indicating the importance of N-terminal HTT in selective neuropathology. That said, homozygous N160Q-KI mice are also embryonic lethal, suggesting that N-terminal HTT alone is unable to support embryonic development. Using Htt knockout neurons, we found that loss of Htt selectively affects the survival of developing neuronal cells, but not astrocytes, in culture. This neuronal degeneration could be rescued by a truncated HTT lacking the first 237 amino acids, but not by N-terminal HTT (1–208 amino acids). Also, the rescue effect depends on the region in HTT known to be involved in intracellular trafficking. Thus, the N-terminal HTT region may not be essential for the survival of developing neurons, but when carrying a large polyQ repeat, can cause selective neuropathology. These findings imply a possible therapeutic benefit of removing the N-terminal region of HTT containing the polyQ repeat to treat the neurodegeneration in HD.