DEVELOPMENT OF CELLULAR & ANIMAL MODELS FOR HUNTINGTONS

亨廷顿病(HD)是一种常染色体显性遗传性进行性神经退行性疾病，一般在中年发病。HD的特点是舞蹈症、痴呆症和神经精神问题。突变在于扩增一个多态的CAG重复序列，导致HD基因产物(Huntingtin)N端的多聚谷氨酰胺长度超过正常长度，这是一种功能未知的突变。我们已经创建了HD的小鼠模型，它概括了人类疾病固有的行为异常和神经病理变化的特征。这些携带重复扩张的小鼠表现出渐进性行为，从运动亢进到运动不足和运动停滞。病理上，神经元表现为早期的树突状变化，最终导致细胞凋亡和细胞丢失。我们已经确定了这些小鼠受影响神经元的形态变化，这些变化标志着发病的早期事件，并且这些变化独立地得到了分子和生化方法的支持，这些方法使用cDNA微阵列和囊泡蛋白和细胞骨架的免疫细胞化学染色。突变的亨廷顿蛋白与这些蛋白质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该小组深入研究的主题。这些研究将有助于更好地了解大脑功能，因为它与认知、情绪和神经元生存有关；并可能导致更好的治疗HD和其他大脑退行性疾病的方案。

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.