Circ-Hdgfrp3 shuttles along neurites and is trapped in aggregates formed by ALS-associated mutant FUS
Circ-Hdgfrp3 shuttles along neurites and is trapped in aggregates formed by ALS-associated mutant FUS
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DOI：
10.1016/j.isci.2021.103504
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发表时间：
2021-12-17
期刊：
影响因子：
5.8
通讯作者：
Bozzoni, Irene
中科院分区：
文献类型：
--
作者：
D'Ambra, Eleonora;Santini, Tiziana;Bozzoni, Irene
CircRNA属于进化保守的RNA分子家族，具有组织特异性表达，并且在神经元细胞中丰富。在这里，我们定义了几个功能的circ-Hdgfrp 3和描述有趣的变化发生在运动神经元（MN）携带ALS相关的FUS突变。通过一个高度敏感的原位方法，我们描述了circ-Hdgfrp 3交通沿着神经突，而在氧化应激时，它被保留在核周区域。而在野生型应激MN中，circ-Hdgfrp 3定位于应激颗粒（SG）中，在携带突变FUS的MN中，更高比例的circ-Hdgfrp 3被捕获到细胞质聚集体中。在应力去除后，circ-Hdgfrp 3容易从SG中释放，而从FUS聚集体中释放的效率较低。我们发现，人类circ-Hdgfrp 3对应物也类似地与应激神经元细胞中的突变型FUS聚集体相关。总的来说，circ-Hdgfrp 3运输的改变为ALS疾病中的FUS聚集体的作用增加了进一步的复杂性。
CircRNAs belong to a family of RNA molecules which are conserved in evolution, have tissue-specific expression, and are abundant in neuronal cells. Here, we define several features of circ-Hdgfrp3 and describe interesting alterations occurring in motor neurons (MNs) carrying ALS-associated FUS mutations. Through a highly sensitive in situ approach we describe that circ-Hdgfrp3 traffics along neurites, while upon oxidative stress it is retained in the perinuclear region. While in wild-type stressed MNs, circ-Hdgfrp3 localizes in stress granules (SGs), in MNs carrying mutant FUS, a higher proportion of circ-Hdgfrp3 was trapped into cytoplasmic aggregates. Upon stress removal, circ-Hdgfrp3 was easily freed from SGs whereas it was less efficiently released from FUS-aggregates. We found that the human circ-Hdgfrp3 counterpart was also similarly associated to mutant FUS-aggregates in stressed neuronal cells. Overall, the alteration of circ-Hdgfrp3 trafficking adds a further layer of complexity to the role of FUS-aggregates in ALS disease.