A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila
A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila
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DOI：
10.1073/pnas.2628045100
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发表时间：
2003-05-13
影响因子：
11.1
通讯作者：
Thompson, LM
中科院分区：
文献类型：
--
作者：
Apostol, BL;Kazantsev, A;Thompson, LM
含有聚谷氨酰胺的聚集体和包涵体的形成是亨廷顿病发病机制的标志，其可以在模型系统中重现。尽管包涵体对发病机制的贡献尚不清楚，但基于细胞的测定可用于筛选影响聚集并可提供治疗益处的化合物。我们已经开发了诱导型PC12细胞培养模型来筛选可见聚集体的丢失。为了测试该方法的有效性，在多聚谷氨酰胺重复疾病的果蝇模型中测试了在基于PC12细胞的筛选中抑制聚集的化合物。PC12细胞聚集的破坏与果蝇神经元变性的抑制密切相关。因此，与果蝇模型偶联的工程化的PC12细胞提供了筛选和验证化合物的快速且有效的方法。
The formation of polyglutamine-containing aggregates and inclusions are hallmarks of pathogenesis in Huntington's disease that can be recapitulated in model systems. Although the contribution of inclusions to pathogenesis is unclear, cell-based assays can be used to screen for chemical compounds that affect aggregation and may provide therapeutic benefit. We have developed inducible PC12 cell-culture models to screen for loss of visible aggregates. To test the validity of this approach, compounds that inhibit aggregation in the PC12 cell-based screen were tested in a Drosophila model of polyglutamine-repeat disease. The disruption of aggregation in PC12 cells strongly correlates with suppression of neuronal degeneration in Drosophila. Thus, the engineered PC12 cells coupled with the Drosophila model provide a rapid and effective method to screen and validate compounds.