Modeling Huntington's Disease in Drosophila

描述（由申请人提供）：亨廷顿氏病是一种常染色体显性神经退行性疾病，由亨廷顿蛋白中聚谷氨酰胺束的扩张引起，导致细胞内聚集形成和神经退行性变。从聚谷氨酰胺束扩张到疾病发病机制的途径仍然不清楚。为了阐明聚谷氨酰胺扩增如何导致神经元功能障碍，我们已经产生了表达人类亨廷顿蛋白cdna的果蝇转基因菌株，编码致病性或非致病性蛋白。虽然非致病性亨廷顿蛋白的表达对行为、寿命或神经元形态没有明显的影响，但含有Q128通道的亨廷顿蛋白的泛神经元表达会导致运动协调能力的逐渐丧失、寿命的缩短和亨廷顿蛋白聚集体的时间依赖性形成，特别是在细胞质和神经突中。亨廷顿蛋白聚集体在细胞质中隔离其他扩大的聚谷氨酰胺蛋白，并导致突触聚集体积聚和轴突运输的中断。相比之下，果蝇单独表达扩大的聚谷氨酰胺束，或者在脊髓小脑共济失调3型蛋白的背景下表达扩大的聚谷氨酰胺束，只显示核聚集体，不破坏轴突运输。我们建议扩展这些研究，以确定细胞质亨廷顿蛋白聚集诱导的非核事件如何导致亨廷顿病中观察到的进行性神经变性。此外，我们将描述天然亨廷顿蛋白在体内的作用，并筛选亨廷顿蛋白聚集的直接抑制因子。总之，这些方法应该扩大我们对亨廷顿蛋白正常功能的理解，并为亨廷顿病的发病机制提供新的见解。

DESCRIPTION (provided by applicant): Huntington's disease is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein that results in intracellular aggregate formation and neurodegeneration. Pathways leading from polyglutamine tract expansion to disease pathogenesis remain obscure. To elucidate how polyglutamine expansion causes neuronal dysfunction, we have generated Drosophila transgenic strains expressing human huntingtin cDNAs encoding pathogenic or nonpathogenic proteins. While expression of nonpathogenic huntingtin has no discernible effect on behavior, lifespan or neuronal morphology, pan-neuronal expression of huntingtin containing a Q128 tract causes a progressive loss of motor coordination, decreased lifespan and time-dependent formation of huntingtin aggregates specifically in the cytoplasm and neurites. Huntingtin aggregates sequester other expanded polyglutamine proteins in the cytoplasm and lead to synaptic aggregate accumulation and disruption of axonal transport. In contrast, Drosophila expressing an expanded polyglutamine tract alone, or an expanded polyglutamine tract in the context of the spinocerebellar ataxia type 3 protein, display only nuclear aggregates and do not disrupt axonal trafficking. We propose to expand upon these studies to determine how non-nuclear events induced by cytoplasmic huntingtin aggregation may cause the progressive neurodegeneration observed in Huntington's disease. In addition, we will characterize the in vivo role of the native huntingtin protein and screen for direct suppressors of huntingtin aggregation. Together, these approaches should expand our understanding of the normal function of the huntingtin protein, as well as provide novel insights into the pathogenesis of Huntington's Disease.