TRIPLET REPEAT DISEASE: REQUIREMENT FOR CASPASE CLEAVAGE

这些研究的长期目标是开发一种有效的治疗方法，用于治疗由CAG重复序列扩张引起的以遗传为主的、起病晚的神经退行性疾病。CAG/聚谷氨酰胺的扩张已被发现形成了至少七种神经退行性疾病的分子基础。这些疾病包括亨廷顿病(HD)、脊髓和延髓肌肉萎缩症(SBMA、肯尼迪病)、马查多-约瑟夫病(MJD或SCA-3)、齿状回苍白球核萎缩(DRPLA)以及脊髓小脑性共济失调1、2和6型(SCA-1、SCA-2和SCA-6)。在所有病例中，不同脑区的神经元都有选择性死亡，临床症状与受累区域相关。这些致病蛋白中的大多数功能尚不清楚，除了聚谷氨酰胺束外，这些蛋白似乎在功能上是无关的。所有这些蛋白质中谷氨酰胺重复序列的扩展似乎赋予了疾病蛋白质一种有毒的功能获得，这对神经元是有选择性的有害的。这项拟议研究的目标是确定这七种疾病相关基因产物之间的共同关系。我们将检验我们的假设，即七种含有聚谷氨酰胺的蛋白质是促凋亡的，并且促凋亡的表型依赖于细胞死亡执行者caspase对这些蛋白质的切割。

The long-term objective of these studies is to develop an effective therapy for dominantly inherited, late onset, neurodegenerative diseases caused by expansions in CAG repeats. The CAG/polyglutamine expansion has been found to form the molecular basis for at least seven neurodegenerative diseases. These include Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA, Kennedy's disease), Machado-Joseph disease (MJD or SCA-3), dentatorubropallidoluysian atrophy (DRPLA), and spinocerebellar ataxias types 1, 2, and 6 (SCA-1, SCA-2, and SCA-6). In all cases, there is selective death of neurons in different brain regions and the clinical symptoms correlate with the affected regions. The function of most of these disease causing proteins is unknown and the proteins appear to be functionally unrelated except for the polyglutamine tract. Expansion of the glutamine repeat in all these proteins appears to confer upon the disease protein a toxic gain-of-function that is selectively deleterious to neurons. The goal of the proposed research is to define a common relationship between these seven disease-associated gene products. We will test our hypothesis that the seven polyglutamine containing proteins are pro-apoptotic, and that the pro-apoptotic phenotype is dependent upon cleavage of these proteins by cell death executioners, the caspases.