Neuron：亨廷顿病研究取得进展

　　

　亨廷顿病（HD）是重要的神经退行性疾病，此病与一系列重大神经退行性疾病，如老年痴呆、帕金森病都很相似。亨廷顿病是典型的遗传性疾病，因而成为神经退行性疾病研究的热点。科学家们期望通过对亨廷顿病的研究能找出针对神经退行性疾病治疗的有效方法。

　　先前的研究报道主要着重于亨廷顿病中基因突变产生的变性蛋白导致脑内神经细胞死亡的机制方面。然而脑组织近90%的细胞为胶质细胞。这些胶质细胞为神经细胞提供营养及保护神经细胞。亨廷顿病中变性蛋白是否通过影响胶质细胞而造成神经细胞的损伤尚不清楚。

　　中国科学院遗传与发育生物学研究所李晓江研究组曾在美国Emory大学建立了新型转基因小鼠HD模型。这些小鼠模型在少突胶质细胞里能特异性地表达HD变异蛋白。在以上工作基础上他们又进行了更深入的研究，发现这些HD变异蛋白只影响成熟分化后的少突胶质细胞及髓鞘蛋白的产生，从而导致神经轴突变性及小鼠神经运动障碍症状。此研究提示成年后少突胶质细胞的替代与功能修复可为治疗HD疾病提供新型治疗途经。该研究结果于3月18日在线发表在Neuron 杂志上。

　　该文通迅作者为遗传发育所研究员李晓江及该所访问学者、研究员李世华。李晓江实验室的博士研究生王国昊也参与了此工作。此工作受到分子生物发育学国家重点实验室的资助。

原文摘要：

Mutant Huntingtin Downregulates Myelin Regulatory Factor-Mediated Myelin Gene Expression and Affects Mature Oligodendrocytes

Growing evidence indicates that non-neuronal mutant huntingtin toxicity plays an important role in Huntington’s disease (HD); however, whether and how mutant huntingtin affects oligodendrocytes, which are vitally important for neural function and axonal integrity, remains unclear. We first verified the presence of mutant huntingtin in oligodendrocytes in HD140Q knockin mice. We then established transgenic mice (PLP-150Q) that selectively express mutant huntingtin in oligodendrocytes. PLP-150Q mice show progressive neurological symptoms and early death, as well as age-dependent demyelination and reduced expression of myelin genes that are downstream of myelin regulatory factor (MYRF or MRF), a transcriptional regulator that specifically activates and maintains the expression of myelin genes in mature oligodendrocytes. Consistently, mutant huntingtin binds abnormally to MYRF and affects its transcription activity. Our findings suggest that dysfunction of mature oligodendrocytes is involved in HD pathogenesis and may also make a good therapeutic target.