Disruption of axonal transport by loss of huntingtin or expression of pathogenic PolyQ proteins in Drosophila
Disruption of axonal transport by loss of huntingtin or expression of pathogenic PolyQ proteins in Drosophila
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DOI：
10.1016/s0896-6273(03)00594-4
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发表时间：
2003-09-25
期刊：
影响因子：
16.2
通讯作者：
Goldstein, LSB
中科院分区：
文献类型：
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作者：
Gunawardena, S;Her, LS;Goldstein, LSB
我们测试了与亨廷顿舞蹈症和其他聚谷氨酰胺 (polyQ) 扩张疾病相关的蛋白质是否会导致轴突运输缺陷。果蝇亨廷顿蛋白的减少和含有致病性 PolyQ 重复序列的蛋白质表达的减少会破坏轴突运输。致病性polyQ蛋白在轴突和核内含物中积累，滴定可溶性运动蛋白，并导致神经元凋亡和生物体死亡。细胞质polyQ重复蛋白的表达会导致成年视网膜变性、幼虫神经元轴突阻塞和幼虫死亡，但不会导致神经元凋亡或核内含物。核内的polyQ重复蛋白会诱导神经元凋亡和幼虫致死，但不会导致轴突阻塞。我们认为致病性 PolyQ 蛋白通过两种非相互排斥的机制导致神经元功能障碍和机体死亡。一种机制需要细胞核积累并诱导细胞凋亡；另一种机制需要细胞核积累并诱导细胞凋亡。另一个干扰轴突运输。因此，致病性polyQ蛋白对轴突运输的破坏可能有助于亨廷顿舞蹈症和其他polyQ扩张疾病的早期神经病理学。
We tested whether proteins implicated in Huntington's and other polyglutamine (polyQ) expansion diseases can cause axonal transport defects. Reduction of Drosophila huntingtin and expression of proteins containing pathogenic polyQ repeats disrupt axonal transport. Pathogenic polyQ proteins accumulate in axonal and nuclear inclusions, titrate soluble motor proteins, and cause neuronal apoptosis and organismal death. Expression of a cytoplasmic polyQ repeat protein causes adult retinal degeneration, axonal blockages in larval neurons, and larval lethality, but not neuronal apoptosis or nuclear inclusions. A nuclear polyQ repeat protein induces neuronal apoptosis and larval lethality but no axonal blockages. We suggest that pathogenic polyQ proteins cause neuronal dysfunction and organismal death by two non-mutually exclusive mechanisms. One mechanism requires nuclear accumulation and induces apoptosis; the other interferes with axonal transport. Thus, disruption of axonal transport by pathogenic polyQ proteins could contribute to early neuropathology in Huntington's and other polyQ expansion diseases.