The implications of neural DNA damage in neurodegeneration

神经 DNA 损伤在神经退行性疾病中的影响

• 批准号: 2098662
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2098662
• 关键词: implications; neural; DNA; damage; neurodegeneration

Cells respond to DNA damage by pausing the cell cycle and mounting repair processes. High levels of damage or non-repairable damage can trigger apoptosis. These responses to DNA damage help to reduce the risk of damaged chromosomes or mutations being passed to daughter cells and the risk of cancer. Double-stand breaks to chromosomes are the most deleterious type of DNA damage. They are repaired by the error-prone process of non-homologous end-joining during the G1 phase of the cell-cycle. Additionally, homologous recombination can be employed during M- and S-phases using the sister chromatid as a template to repair the break. In post-mitotic, non-cycling neurons, homologous recombination is not available so double-strand breaks are repaired by non-homologous end-joining.Double-strand breaks (DSBs) are generated in neurons during normal physiological activity. In mice placed in a novel environment DSBs form but are rapidly repaired, potentially due to upregulation of metabolic activity during exploration of the new environment. However, in disease scenarios, DSBs form to excess and are not completely repaired. DNA damage is also likely to accumulate in neurons during healthy ageing. The consequence is chronic activation of the DNA damage response. We have demonstrated that attenuating the DNA damage response can reduce neuropathology and support neural function multiple different models of neuropathology and in both invertebrate and vertebrate models. This argues that chronic activation of the DNA damage responses in the ageing brain may be contribute to declining neural health with age, and to the neuropathology of neurodegenerative diseases.This project aims to understand why neurons respond to DNA damage in the way they do. What occurs in neurons when the DNA damage response is activated that leads to impacts on neural health and causes neural dysfunction? Using Drosophila, we will aim to identify the cellular events occurring downstream of activation of the DNA damage response and to identify which components of the DNA damage responses are important for neural health.

细胞对DNA损伤的反应是暂停细胞周期并启动修复过程。高水平的损伤或不可修复的损伤可触发细胞凋亡。这些对DNA损伤的反应有助于降低受损染色体或突变传递给子细胞的风险以及癌症的风险。染色体的双链断裂是最有害的DNA损伤类型。它们在细胞周期的G1期通过非同源末端连接的易错过程修复。此外，同源重组可以在M期和S期使用姐妹染色单体作为模板来修复断裂。在有丝分裂后的非周期性神经元中，同源重组不可用，因此双链断裂通过非同源末端连接来修复。在置于新环境中的小鼠中，DSB形成但迅速修复，这可能是由于在探索新环境期间代谢活性的上调。然而，在疾病情况下，DSB形成过多并且没有完全修复。在健康的衰老过程中，DNA损伤也可能在神经元中积累。结果是DNA损伤反应的慢性激活。我们已经证明，在无脊椎动物和脊椎动物模型中，减弱DNA损伤反应可以减少神经病理学并支持神经功能。这表明，衰老大脑中DNA损伤反应的慢性激活可能导致神经健康随年龄增长而下降，并导致神经退行性疾病的神经病理学。本项目旨在了解神经元对DNA损伤的反应方式。当DNA损伤反应被激活时，神经元中会发生什么，导致对神经健康的影响并导致神经功能障碍？使用果蝇，我们的目标是识别DNA损伤反应激活下游发生的细胞事件，并确定DNA损伤反应的哪些成分对神经健康很重要。