DEVELOPMENT OF CELLULAR & ANIMAL MODELS FOR HUNTINGTONS

亨廷顿氏病（HD）是一种常染色体显性进行性神经退行性疾病，通常在中年发病。HD的特点是舞蹈病、痴呆和神经精神问题。突变在于多态CAG重复扩增，导致HD基因产物（亨廷顿蛋白）n端多聚谷氨酰胺的长度大于正常长度，其功能未知。我们已经创建了HD小鼠模型，这些模型概括了人类疾病固有的行为异常和神经病理变化的特征。这些携带重复扩增的小鼠表现出从运动过度到运动不足和运动不足的进行性行为。病理上，神经元表现出早期树突状改变，最终导致细胞凋亡和细胞丢失。我们已经在这些小鼠的受影响神经元中发现了形态学变化，这些变化标志着发病的早期事件，这些变化得到了分子和生化方法的独立支持，这些方法使用cDNA微阵列和免疫细胞化学染色检测水泡蛋白和细胞骨架。突变的亨廷顿蛋白与这些蛋白的相互作用，以及这些相互作用如何导致神经退行性变化是这个小组深入研究的主题。这些研究将使我们更好地理解大脑功能，因为它与认知、情感和神经元存活有关；并可能为HD和其他大脑退行性疾病提供更好的治疗方案。

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder with onset generally in midlife. HD is characterized by chorea, dementia, and neuropsychiatric problems. The mutation lies in the expansion of a polymorphic CAG repeat resulting in greater than normal length of polyglutamines in the N-terminal end of the HD gene product (huntingtin) which is of unknown function. We have created mouse models for HD that recapitulates features of behavioral abnormalities and neuropathological changes inherent in the human disease. These mice carrying the repeat expansions show progressive behavior going from hyperkinesia to hypokinesia and akinesia. Pathologically, neurons show early dendritic changes cumlminating in apoptotic changes and cell loss. We have identified morphological changes in affected neurons of these mice that mark early events of pathogenesis and these changes are supported independently by molecular and biochemical approaches using cDNA microarrays and immunocytochemical stains for vesicular proteins and cytoskeleton. The interplay of mutant huntingtin with these proteins and how these interactions could lead to neurodegenertaive changes are the subject of intense investigation by this group. These studies will lead to a better understanding of brain function as it relates to cognition, emotions, and neuronal survival; and may lead to better therapeutic regimens for HD and other degenerative disorders of the brain.