Polyglutamine (polyQ) diseases, such as Spinocerebellar ataxia type 7 (SCA7), are caused by expansions of polyQ repeats in disease specific proteins. The sequestration of vital proteins into aggregates formed by polyQ proteins is believed to be a common pathological mechanism in these disorders. The RNA-binding protein FUS has been observed in polyQ aggregates, though if disruption of this protein plays a role in the neuronal dysfunction in SCA7 or other polyQ diseases remains unclear. We therefore analysed FUS localisation and function in a stable inducible PC12 cell model expressing the SCA7 polyQ protein ATXN7. We found that there was a high degree of FUS sequestration, which was associated with a more cytoplasmic FUS localisation, as well as a decreased expression of FUS regulated mRNAs. In contrast, the role of FUS in the formation of γH2AX positive DNA damage foci was unaffected. In fact, a statistical increase in the number of γH2AX foci, as well as an increased trend of single and double strand DNA breaks, detected by comet assay, could be observed in mutant ATXN7 cells. These results were further corroborated by a clear trend towards increased DNA damage in SCA7 patient fibroblasts. Our findings suggest that both alterations in the RNA regulatory functions of FUS, and increased DNA damage, may contribute to the pathology of SCA7.

多聚谷氨酰胺 (polyQ) 疾病，如脊髓小脑性共济失调 7 型 (SCA7)，是由疾病特异性蛋白质中 polyQ 重复序列的扩增引起的。将重要蛋白质隔离成由 polyQ 蛋白质形成的聚集体被认为是这些疾病的常见病理机制。RNA 结合蛋白 FUS 已在 polyQ 聚集体中观察到，但这种蛋白质的破坏是否在 SCA7 或其他 polyQ 疾病的神经元功能障碍中起作用尚不清楚。因此，我们在表达 SCA7 polyQ 蛋白 ATXN7 的稳定诱导型 PC12 细胞模型中分析了 FUS 定位和功能。我们发现存在高度的 FUS 隔离，这与更多的细胞质 FUS 定位以及 FUS 调节的 mRNA 的表达降低有关。相比之下，FUS 在 γH2AX 阳性 DNA 损伤灶形成中的作用不受影响。事实上，在突变的 ATXN7 细胞中可以观察到通过彗星试验检测到的 γH2AX 病灶数量的统计增加以及单链和双链 DNA 断裂的增加趋势。SCA7 患者成纤维细胞中 DNA 损伤增加的明显趋势进一步证实了这些结果。我们的研究结果表明，FUS 的 RNA 调节功能的改变和 DNA 损伤的增加都可能导致 SCA7 的病理学。SCA7 患者成纤维细胞中 DNA 损伤增加的明显趋势进一步证实了这些结果。我们的研究结果表明，FUS 的 RNA 调节功能的改变和 DNA 损伤的增加都可能导致 SCA7 的病理学。SCA7 患者成纤维细胞中 DNA 损伤增加的明显趋势进一步证实了这些结果。我们的研究结果表明，FUS 的 RNA 调节功能的改变和 DNA 损伤的增加都可能导致 SCA7 的病理学。