Ona V O, Li M, Vonsattel J P, Andrews L J, Khan S Q, Chung W M, Frey A S, Menon A S, Li X J, Stieg P E, Yuan J, Penney J B, Young A B, Cha J H, Friedlander R M
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 1999 May 20;399(6733):263-7. doi: 10.1038/20446.
Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex. The disease is universally fatal, with a mean survival following onset of 15-20 years and, at present, there is no effective treatment. The mutation in patients with Huntington's disease is an expanded CAG/polyglutamine repeat in huntingtin, a protein of unknown function with a relative molecular mass of 350,000 (M(r) 350K). The length of the CAG/polyglutamine repeat is inversely correlated with the age of disease onset. The molecular pathways mediating the neuropathology of Huntington's disease are poorly understood. Transgenic mice expressing exon 1 of the human huntingtin gene with an expanded CAG/polyglutamine repeat develop a progressive syndrome with many of the characteristics of human Huntington's disease. Here we demonstrate evidence of caspase-1 activation in the brains of mice and humans with the disease. In this transgenic mouse model of Huntington's disease, expression of a dominant-negative caspase-1 mutant extends survival and delays the appearance of neuronal inclusions, neurotransmitter receptor alterations and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of the disease. In addition, we demonstrate that intracerebroventricular administration of a caspase inhibitor delays disease progression and mortality in the mouse model of Huntington's disease.
亨廷顿舞蹈病是一种常染色体显性进行性神经退行性疾病，会导致纹状体和皮质中的特定神经元丧失及功能障碍。该疾病普遍致命，发病后的平均生存期为15至20年，目前尚无有效治疗方法。亨廷顿舞蹈病患者的突变是亨廷顿蛋白中CAG/多聚谷氨酰胺重复序列的扩增，亨廷顿蛋白是一种功能未知、相对分子质量为350,000（Mr 350K）的蛋白质。CAG/多聚谷氨酰胺重复序列的长度与疾病发病年龄呈负相关。介导亨廷顿舞蹈病神经病理学的分子途径目前了解甚少。表达带有扩增CAG/多聚谷氨酰胺重复序列的人类亨廷顿蛋白基因外显子1的转基因小鼠会出现一种进行性综合征，具有许多人类亨廷顿舞蹈病的特征。在此，我们证明了患有该疾病的小鼠和人类大脑中存在半胱天冬酶-1激活的证据。在这个亨廷顿舞蹈病的转基因小鼠模型中，显性负性半胱天冬酶-1突变体的表达延长了生存期，并延迟了神经元内含物、神经递质受体改变及症状发作的出现，这表明半胱天冬酶-1在该疾病的发病机制中很重要。此外，我们证明向脑室内注射半胱天冬酶抑制剂可延缓亨廷顿舞蹈病小鼠模型的疾病进展和死亡率。
