Modeling Huntington's Disease in Drosophila

果蝇亨廷顿舞蹈病模型

基本信息

批准号：
6954283
负责人：
J. TROY LITTLETON
金额：
$ 36.42万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6954283
关键词：
Drosophilidae Huntington&apos s disease cerebellar ataxia /dyskinesia complementary DNA confocal scanning microscopy disease /disorder model electrophysiology green fluorescent proteins microarray technology nerve /myelin protein neural degeneration pathologic process transmission electron microscopy

项目摘要

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.

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，由亨廷顿蛋白中的聚谷氨酰胺链扩张引起，导致细胞内聚集体形成和神经变性。从多聚谷氨酰胺束扩张到疾病发病机制的途径仍然不清楚。为了阐明多聚谷氨酰胺扩增如何导致神经元功能障碍，我们产生了表达编码致病性或非致病性蛋白质的人类亨廷顿蛋白cDNA的果蝇转基因菌株。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影响，但含有 Q128 束的亨廷顿蛋白的泛神经元表达会导致运动协调性逐渐丧失、寿命缩短以及亨廷顿蛋白聚集物的时间依赖性形成，特别是在细胞质和细胞质中。神经突。亨廷顿蛋白聚集体将其他扩展的聚谷氨酰胺蛋白隔离在细胞质中，并导致突触聚集体积累和轴突运输的破坏。相反，果蝇单独表达扩展的聚谷氨酰胺束，或在脊髓小脑共济失调3型蛋白的背景下表达扩展的聚谷氨酰胺束，仅显示核聚集体并且不破坏轴突运输。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，我们将表征天然亨廷顿蛋白的体内作用，并筛选亨廷顿蛋白聚集的直接抑制剂。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。