Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
Department of Biomedicine, Aarhus University, 8000, Aarhus, Denmark.
Cell Mol Neurobiol. 2023 Jan;43(1):237-249. doi: 10.1007/s10571-021-01163-7. Epub 2021 Nov 6.
SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking out SORCS2 in a human neuronal cell line increased Topoisomerase IIβ-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaks in vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.
SORCS2 是构成 Vps10p 结构域受体家族的五种蛋白之一。该家族的成员在与神经元存活、分化和功能相关的细胞过程中发挥着重要作用。遗传和功能研究表明，SORCS2 与认知功能以及神经退行性和精神疾病有关。DNA 损伤和 DNA 修复缺陷与衰老和神经退行性变有关，神经元活动也会导致瞬时神经元双链断裂 (DSB)。在这里，我们报告了 SORCS2 在 DSB 形成中的一个新作用。我们表明 SorCS2 缺失与小鼠齿状回中 DSB 水平升高有关，并且在人类神经元细胞系中敲除 SORCS2 会增加拓扑异构酶 IIβ 依赖性 DSB 形成并降低神经元活力。体外神经元刺激对 DNA 断裂水平没有影响，这表明观察到的差异可能不是这些细胞中异常神经元活动的结果。我们的研究结果与将 VPS10 受体与 DNA 损伤与神经退行性疾病联系起来的研究一致。
