Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease
Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease
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DOI：
10.1073/pnas.0400243101
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发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Littleton, JT
中科院分区：
文献类型：
--
作者：
Lee, WCM;Yoshihara, M;Littleton, JT
亨廷顿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束扩张导致细胞内聚集体形成和神经变性引起。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，我们生成了表达编码致病性（Htt-Q128）或非致病性蛋白（Htt-Q0）的人类亨廷顿蛋白cDNA的果蝇转基因菌株。虽然 Htt-Q0 的表达对行为、寿命或神经元形态没有明显影响，但 Htt-Q128 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。亨廷顿蛋白聚集体将其他扩展的聚谷氨酰胺蛋白隔离在细胞质中，并导致轴突运输的破坏和突触处聚集体的积累。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。我们的研究结果表明，细胞质亨廷顿蛋白聚集诱导的非核事件在亨廷顿病中观察到的进行性神经变性中发挥着核心作用。
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 generated Drosophila transgenic strains expressing human huntingtin cDNAs encoding pathogenic (Htt-Q128) or nonpathogenic proteins (Htt-Q0). Whereas expression of Htt-Q0 has no discernible effect on behavior, lifespan, or neuronal morphology, pan-neuronal expression of Htt-Q128 leads to 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 disruption of axonal transport and accumulation of aggregates at synapses. 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. Our findings indicate that nonnuclear events induced by cytoplasmic huntingtin aggregation play a central role in the progressive neurodegeneration observed in Huntington's disease.