Li X J, Li S H, Sharp A H, Nucifora F C, Schilling G, Lanahan A, Worley P, Snyder S H, Ross C A
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nature. 1995 Nov 23;378(6555):398-402. doi: 10.1038/378398a0.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanding polyglutamine repeat in the IT15 or huntingtin gene. Although this gene is widely expressed and is required for normal development, the pathology of HD is restricted to the brain, for reasons that remain poorly understood. The huntingtin gene product is expressed at similar levels in patients and controls, and the genetics of the disorder suggest that the expansion of the polyglutamine repeat induces a toxic gain of function, perhaps through interactions with other cellular proteins. Here we report the identification of a protein (huntingtin-associated protein (HAP)-1) that binds to huntingtin. This binding is enhanced by an expanded polyglutamine repeat, the length of which is also known to correlate with the age of disease onset. The HAP-1 protein is enriched in the brain, suggesting a possible basis for the selective brain pathology of HD.
亨廷顿舞蹈症（HD）是一种常染色体显性神经退行性疾病，由IT15基因（亦称亨廷顿基因）中的多聚谷氨酰胺重复序列扩展所致。尽管该基因广泛表达且对正常发育至关重要，但HD的病理变化却局限于大脑，其原因仍知之甚少。亨廷顿基因产物在患者和对照组中的表达水平相似，该疾病的遗传学研究表明，多聚谷氨酰胺重复序列的扩展可能通过与其他细胞蛋白相互作用，导致功能获得性毒性。在此，我们报告了一种与亨廷顿蛋白结合的蛋白（亨廷顿相关蛋白（HAP）-1）的鉴定结果。这种结合因多聚谷氨酰胺重复序列的扩展而增强，而该序列的长度也与疾病发病年龄相关。HAP-1蛋白在大脑中富集，这提示了HD选择性脑病理变化的一个可能原因。
