The implications of neural DNA damage in neurodegeneration

细胞通过暂停细胞周期和修复过程来应对DNA损伤。高水平的损伤或不可修复的损伤会引发细胞凋亡。这些对DNA损伤的反应有助于降低染色体受损或突变传递给子代细胞的风险，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。在细胞周期的G1期，它们通过容易出错的非同源末端连接过程进行修复。此外，同源重组可以在M期和S期进行，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神经元中，同源重组是不存在的，因此双链断裂可以通过非同源末端连接来修复。在正常的生理活动中，神经元会产生双链断裂。在放置在新环境中的小鼠中，DSB形成但很快修复，可能是由于在探索新环境期间代谢活动上调所致。然而，在疾病的情况下，双链断裂形成过度，并且不能完全修复。在健康老化的过程中，DNA损伤也可能在神经元中积累。其结果是DNA损伤反应的慢性激活。我们已经证明，减弱DNA损伤反应可以减少神经病理并支持神经功能多种不同的神经病理模型，以及在无脊椎动物和脊椎动物模型中。这一观点认为，老化大脑中DNA损伤反应的慢性激活可能是导致神经健康状况随年龄下降，以及神经退行性疾病的神经病理学的原因之一。该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，从而对神经健康造成影响，并导致神经功能障碍？以果蝇为例，我们的目标是确定DNA损伤反应激活后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至关重要。

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.