Combined deficiency of Senataxin and DNA-PKcs causes DNA damage accumulation and neurodegeneration in spinal muscular atrophy
Combined deficiency of Senataxin and DNA-PKcs causes DNA damage accumulation and neurodegeneration in spinal muscular atrophy
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DOI：
10.1093/nar/gky641
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发表时间：
2018-09-19
影响因子：
14.9
通讯作者：
Gangwani, Laxman
中科院分区：
文献类型：
--
作者：
Kannan, Annapoorna;Bhatia, Kanchan;Gangwani, Laxman
运动神经元存活蛋白（SMN）长期处于低水平会导致脊髓性肌萎缩症（SMA）。 SMN 普遍表达，但 SMA 中主要神经元变性的机制尚不清楚。我们报告说，长期低水平的 SMN 会导致 Senataxin (SETX) 缺乏，从而导致 RNA-DNA 杂合体 (R 环) 和 DNA 双链断裂 (DSB) 增加，以及 DNA 激活蛋白激酶催化亚基 (DNA-PKcs) 缺乏，从而损害 DSB 修复。因此，DNA 损伤会在患者细胞、SMA 小鼠神经元和患者脊髓组织中积累。在分裂细胞中，DSB 通过同源重组 (HR) 和非同源末端连接 (NHEJ) 途径进行修复，但神经元主要使用 NHEJ，而 NHEJ 依赖于 DNA-PKcs 活性。在 SMA 分裂细胞中，HR 修复 DSB 并支持细胞增殖。在 SMA 神经元中，DNA-PKcs 缺陷会导致 NHEJ 介导的修复缺陷，从而导致 DNA 损伤累积和神经变性。 SMN 水平的恢复可挽救 SMA 神经元和患者细胞中的 SETX 和 DNA-PKcs 缺陷以及 DSB 积累。此外，SETX 在 SMA 神经元中的过度表达可减少 R 环和 DNA 损伤，并挽救神经退行性变。我们的研究结果表明，SMN 下游的 SETX 和 DNA-PKcs 联合缺陷是 SMA 中 DSB 积累、基因组不稳定和神经退行性疾病的根本原因，并表明 SETX 作为 SMA 的潜在治疗靶点。
Chronic low levels of survival motor neuron (SMN) protein cause spinalmuscular atrophy (SMA). SMN is ubiquitously expressed, but the mechanisms underlying predominant neuron degeneration in SMA are poorly understood. We report that chronic low levels of SMN cause Senataxin (SETX)-deficiency, which results in increased RNA-DNA hybrids (R-loops) and DNA double-strand breaks (DSBs), and deficiency of DNA-activated protein kinase-catalytic subunit (DNA-PKcs), which impairs DSB repair. Consequently, DNA damage accumulates in patient cells, SMA mice neurons and patient spinal cord tissues. In dividing cells, DSBs are repaired by homologous recombination (HR) and non-homologous end joining (NHEJ) pathways, but neurons predominantly use NHEJ, which relies on DNA-PKcs activity. In SMA dividing cells, HR repairs DSBs and supports cellular proliferation. In SMA neurons, DNA-PKcs-deficiency causes defects in NHEJ-mediated repair leading to DNA damage accumulation and neurodegeneration. Restoration of SMN levels rescues SETX and DNA-PKcs deficiencies and DSB accumulation in SMA neurons and patient cells. Moreover, SETX overexpression in SMA neurons reduces R-loops and DNA damage, and rescues neurodegeneration. Our findings identify combined deficiency of SETX and DNA-PKcs stemming downstream of SMN as an underlying cause of DSBs accumulation, genomic instability and neurodegen eration in SMA and suggest SETX as a potential therapeutic target for SMA.