Does brain trauma cause premature ageing of the nervous system?

脑外伤会导致神经系统过早衰老吗？

• 批准号: BB/W016907/1
• 负责人: Natalia Sanchez-Soriano
• 金额: $ 66.87万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW016907%2F1
• 关键词: Does; brain; trauma; cause; premature

Different environmental factors have been proposed to account for variations in brain ageing at the individual level. Severe to moderate or repetitive mild impacts to the head are now considered the highest environmental risk factor leading to accelerated brain ageing and dementia. Repeated mild head trauma, as occurring in certain sports, initiates a cascade of events that, in the long-term, affect widespread regions of brain tissue and promote neurodegeneration including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The detailed mechanisms by which this occurs are not understood, thus missing out on promising opportunities for treatment and avoidance of brain deterioration. Here we will bridge this gap. A prominent feature of secondary lesions caused by brain trauma, is damage to axons. Axons are the long thin projections of neurons that form the biological cables wiring our nervous system. Within axons, microtubules (MT) are suggested targets of trauma as indicated by mathematical modelling studies and in vitro stretch experiments. Axonal MTs are arranged into parallel bundles that (a) form the structural backbones protecting against mechanical stress and (b) function as highways for life-sustaining axonal transport of materials and organelles from and to the cell body. The nature of MT defects, the mechanistic causes for their breakdown and the downstream consequences for neuronal physiology are little understood, and it needs to be established whether these processes relate to and converge with brain ageing, thus delivering doubly beneficial understanding. Here we provide new opportunities to address these questions, using a newly established model of mild repetitive trauma in the fruit fly Drosophila. Drosophila is one of the most powerful genetic models: it is time- and cost-effective and uniquely amenable to experimentation. Using this model, we observed that repeated mild trauma induces premature features of ageing, familiar to us from our ageing studies. Features include axonal swellings and synaptic decline, breakdown of MTs and changes in mitochondria and autophagosomes. Here we will capitalise on this model to demonstrate two hypotheses: (a) that axonal MT bundle damage is a prime lesion site in trauma; we will study the mechanisms that trigger the breakdown of MTs, and the knock-on effects on organelles, intracellular transport and deterioration of key neuronal functions; (b) that trauma causes premature ageing; we will investigate whether trauma affects similar neuronal components and processes as ageing and use interventions that delay ageing to see if these ameliorate the long term effect of trauma.Our project involves four key objectives. (1) We will establish commonalities between the cell biology of trauma and ageing. (2) We will focus on MT breakdown which is shared by trauma and ageing and identify processes and proteins involved, how their function is impacted by trauma, and whether their positive manipulation can improve trauma pathology. (3) We will assess the impact MT breakdown has on the physiology of neurons, focussing on key organelles: the dynamics, localisation, morphology and function of mitochondria and autophagosomes. Furthermore, we will assess whether MT manipulations can ameliorate pathological aberrations. (4) We will investigate shared mechanisms of trauma and ageing by positively manipulating cellular stressors of ageing and longevity signalling pathways to see whether they improve trauma pathology, as they do in ageing.Based on the high degree of evolutionary conservation of the molecules and mechanisms regulating neuronal cytoskeleton, organelle biology, responses to brain trauma and ageing processes, we expect that the outcomes derived from our work will provide an important understanding that can be useful in a clinical setting.

已经提出了不同的环境因素来说明个体水平的大脑衰老的变化。现在，对头部的严重到中度或重复的轻度影响现在被认为是导致大脑衰老和痴呆症加速的最高环境危险因素。在某些运动中发生的重复轻度头部外伤发生了一系列级联，从长远来看，这些事件会影响脑组织的广泛区域，并促进神经变性，包括阿尔茨海默氏病，帕金森氏病，帕金森氏病和肌萎缩性侧面硬化症。尚不清楚发生这种情况的详细机制，因此缺少有希望的治疗机会和避免大脑恶化的机会。在这里，我们将弥合这一差距。由脑创伤引起的继发性病变的突出特征是轴突的损伤。轴突是神经元的长薄刺，形成了接线我们神经系统的生物电缆。在轴突中，微管（MT）建议创伤靶标，如数学建模研究和体外拉伸实验所示。轴突MT被排列成平行束，（a）形成了防止机械应力的结构骨架，并且（b）起到了维持生命的轴突运输材料和细胞器的轴突运输的高速公路。 MT缺陷的性质，其分解的机理原因以及对神经元生理的下游后果的理解很少，并且需要确定这些过程是否与大脑衰老有关并汇聚，从而提供了双重好处的理解。在这里，我们提供了新建立的轻度重复创伤模型，在果蝇果蝇中使用新成立的轻度重复创伤模型来解决这些问题。果蝇是最强大的遗传模型之一：它是时间和成本效益，并且可以独特地进行实验。使用此模型，我们观察到，重复的轻度创伤会导致衰老研究中熟悉的衰老的过早特征。特征包括轴突肿胀和突触下降，MT的分解以及线粒体和自噬体的变化。在这里，我们将利用该模型来证明两个假设：（a）轴突MT束损伤是创伤中的主要病变部位；我们将研究触发MT崩溃的机制，以及对细胞器，细胞内转运和关键神经元功能恶化的敲高作用； （b）创伤会导致过早衰老；我们将研究创伤是否会影响类似的神经元成分和过程与衰老和使用干预措施，以延迟衰老，以查看它们是否可以改善创伤的长期影响。您的项目涉及四个关键目标。 （1）我们将在创伤和衰老的细胞生物学之间建立共同点。 （2）我们将专注于MT分解，这是由创伤和衰老所共有的，并确定所涉及的过程和蛋白质，其功能如何受到创伤的影响以及它们的阳性操纵是否可以改善创伤病理。 （3）我们将评估MT分解对神经元生理的影响，重点关注关键细胞器：线粒体和自噬体的动力学，定位，形态和功能。此外，我们将评估MT操纵是否可以改善病理畸变。 （4）我们将通过积极操纵衰老和寿命和寿命信号传导途径的细胞应激源来研究创伤和衰老的共同机制从我们的工作中得出的结果将提供一个重要的理解，在临床环境中可能很有用。

项目成果

Whole organism and tissue specific analysis of pexophagy in Drosophila

果蝇自噬的整体和组织特异性分析

• DOI: 10.1101/2023.11.17.567516
• 发表时间: 2023
• 作者: Barone F

Microtubule decay is a driver of neuronal ageing and a promising target for intervention

• DOI: 10.1101/2023.01.11.523590
• 发表时间: 2023-01
• 期刊: bioRxiv
• 作者: Pilar Okenve-Ramos;Rory Gosling;Monika Chojnowska-Monga;Kriti Gupta;Samuel Shields;N. Sánchez-Soriano