Glial and neuronal expression of polyglutamine proteins induce behavioral changes and aggregate formation in Drosophila
Glial and neuronal expression of polyglutamine proteins induce behavioral changes and aggregate formation in Drosophila
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DOI：
10.1002/glia.20098
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发表时间：
2005-01-01
期刊：
影响因子：
6.2
通讯作者：
Pflugfelder, GO
中科院分区：
文献类型：
--
作者：
Kretzschmar, D;Tschäpe, J;Pflugfelder, GO
患有多谷氨酰胺扩张性疾病的患者，如亨廷顿病或几种脊髓小脑性共济失调，首先出现的神经症状可能是在没有神经变性的情况下发生的。因此，行为症状似乎是由神经元功能障碍引起的，而不是细胞死亡。聚谷氨酰胺扩张性疾病的发病机制在很大程度上被视为神经元中的细胞自主过程。然而，这一过程很可能受到胶质细胞生理变化的影响，至少在DRPLA胶质包涵体和胶质细胞死亡的情况下，似乎是发病机制中的一个重要部分。为了在果蝇模型系统中研究这些方面，我们在成年神经系统中表达了多谷氨酰胺蛋白。多聚谷氨酰胺(Q)扩增的(n=78)和非扩增的(n=27)截短的人类ataxin-3的胶质细胞特异性表达导致蛋白聚集体的形成和胶质细胞的死亡。观察细胞死亡前的行为学变化。这表明胶质细胞对聚谷氨酰胺蛋白的毒性作用很敏感。相同结构的神经元表达导致的行为变化类似于神经胶质表达导致的行为变化，但不会导致神经退化。行为缺陷是选择性的，并影响两种不同分析的苍蝇行为。Q78和Q27的神经胶质聚集体和神经元聚集体在发病早期就出现了，并且在电子显微镜下具有纤维状的亚结构。这表明，非扩张拉伸可以引起与扩张拉伸相似的组织和行为症状，但会有显著的延迟。(C)2004年Wiley-Liss公司
Patients with polyglutamine expansion diseases, like Huntington's disease or several spinocerebellar ataxias, first present with neurological symptoms that can occur in the absence of neurodegeneration. Behavioral symptoms thus appear to be caused by neuronal dysfunction, rather than cell death. Pathogenesis in polyglutamine expansion diseases is largely viewed as a cell-autonomous process in neurons. It is likely, however, that this process is influenced by changes in glial physiology and, at least in the case of DRPLA glial inclusions and glial cell death, seems to be an important part in the pathogenesis. To investigate these aspects in a Drosophila model system, we expressed polyglutamine proteins in the adult nervous system. Glial-specific expression of a polyglutamine (Q)-expanded (n = 78) and also a nonexpanded (n = 27) truncated version of human ataxin-3 led to the formation of protein aggregates and glial cell death. Behavioral changes were observed prior to cell death. This reveals that glia is susceptible to the toxic action of polyglutamine proteins. Neuronal expression of the same constructs resulted in behavioral changes similar to those resulting from glial expression but did not cause neurodegeneration. Behavioral deficits were selective and affected two analyzed fly behaviors differently. Both glial and neuronal aggregates of Q78 and Q27 appeared early in pathogenesis and, at the electron microscopic resolution, had a fibrillary substructure. This shows that a nonexpanded stretch can cause similar histological and behavioral symptoms as the expanded stretch, however, with a significant delay. (C) 2004 Wiley-Liss, Inc.