Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Sci Adv. 2022 Sep 16;8(37):eabq2611. doi: 10.1126/sciadv.abq2611. Epub 2022 Sep 14.
DNA double-strand breaks occur in many acute and long-term neurological conditions, including neurodegeneration, neurotrauma, and stroke. Nonrepaired breaks chronically activate the DNA damage response in neurons, leading to neural dysfunction and apoptosis. Here, we show that targeting of the central ATM-Chk2 pathway regulating the response to double-strand breaks slows neural decline in models of chronic neurodegeneration. Inhibitors of ATM-Chk2, but not the parallel ATR-Chk1 pathway, also promote marked, functional recovery after acute central nervous system injury in rats, suggesting that inhibiting nonhomologous end-joining rather than homologous recombination is crucial for neuroprotection. We demonstrate that the Chk2 inhibitor, prexasertib, which has been evaluated in phase 2 clinical trials for cancer, has potent neuroprotective effects and represents a new treatment option to promote functional recovery after spinal cord or optic nerve injury.
DNA 双链断裂发生在许多急性和慢性神经疾病中，包括神经退行性疾病、神经创伤和中风。未修复的断裂会使神经元中 DNA 损伤反应持续激活，导致神经功能障碍和细胞凋亡。在这里，我们发现靶向调节双链断裂反应的中央 ATM-Chk2 途径可以减缓慢性神经退行性疾病模型中的神经衰退。ATM-Chk2 的抑制剂，而不是平行的 ATR-Chk1 途径，也可以促进大鼠中枢神经系统损伤后的显著功能恢复，这表明抑制非同源末端连接而不是同源重组对于神经保护至关重要。我们证明，已经在癌症的 2 期临床试验中进行评估的 Chk2 抑制剂 prexasertib 具有强大的神经保护作用，是一种新的治疗选择，可以促进脊髓或视神经损伤后的功能恢复。
