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重复序列扩增引起的显性遗传、迟发性神经退行性疾病。已发现CAG/聚谷氨酰胺扩增形成至少七种神经退行性疾病的分子基础。这些包括亨廷顿病（HD）、脊髓和延髓肌萎缩（SBMA，肯尼迪病）、马查多-约瑟夫病（MJD或SCA-3）、齿状核红核苍白球路易体萎缩（DRPLA）和脊髓小脑共济失调1、2和6型（SCA-1、SCA-2和SCA-6）。 在所有情况下，不同脑区的神经元都有选择性死亡，临床症状与受影响的区域相关。 大多数这些致病蛋白质的功能是未知的，除了多聚谷氨酰胺束外，这些蛋白质似乎在功能上不相关。所有这些蛋白质中谷氨酰胺重复序列的扩增似乎赋予疾病蛋白质一种选择性地对神经元有害的毒性功能获得性。 这项研究的目的是确定这七种疾病相关基因产物之间的共同关系。 我们将测试我们的假设，即七个多聚谷氨酰胺含有蛋白质是促凋亡，促凋亡表型是依赖于这些蛋白质的细胞死亡刽子手，半胱天冬酶裂解。

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.