Modeling Huntington's Disease in Drosophila

描述(申请人提供)：亨廷顿病是一种常染色体显性遗传性神经退行性疾病，由亨廷顿蛋白中的多谷氨酰胺束扩张引起，导致细胞内聚集形成和神经变性。从聚谷氨酰胺束扩张到疾病发病机制的途径仍然不清楚。为了阐明多谷氨酰胺扩张是如何导致神经元功能障碍的，我们培育了表达人类亨廷顿蛋白cDNA的果蝇转基因株，编码致病或非致病蛋白。虽然非致病性Huntingtin的表达对行为、寿命或神经元形态没有明显影响，但含有Q128区的Huntingtin的泛神经元表达导致运动协调性进行性丧失，寿命缩短，并在细胞质和轴突中形成特异性的Huntingtin聚集体。亨廷顿蛋白聚集在细胞质中，隔离其他扩张的聚谷氨酰胺蛋白，导致突触聚集和轴突运输中断。相反，单独表达扩展的聚谷氨酰胺束的果蝇，或者在脊髓小脑型共济失调3型蛋白的背景下表达扩展的聚谷氨酰胺束的果蝇，只显示核聚集体，不干扰轴突运输。我们建议扩展这些研究，以确定细胞质亨廷顿蛋白聚集引起的非核事件如何导致亨廷顿病所观察到的进行性神经变性。此外，我们还将研究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，这些方法应该会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.