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.

不同的环境因素已经被提出来解释个体水平上大脑老化的变化。严重到中度或重复的轻微头部撞击现在被认为是导致大脑加速老化和痴呆症的最高环境风险因素。重复的轻度头部创伤，如在某些运动中发生的，引发一系列事件，从长远来看，影响脑组织的广泛区域并促进神经退行性疾病，包括阿尔茨海默病，帕金森病和肌萎缩性侧索硬化症。这种情况发生的详细机制尚不清楚，因此错过了治疗和避免大脑退化的有希望的机会。在这里，我们将弥合这一差距。脑外伤引起的继发性病变的一个突出特征是轴突损伤。轴突是神经元细长的突起，形成连接我们神经系统的生物电缆。在轴突内，微管（MT）被认为是创伤的目标，如数学建模研究和体外拉伸实验所示。轴突MT排列成平行束，其（a）形成保护免受机械应力的结构骨架，和（B）用作维持生命的轴突运输材料和细胞器进出细胞体的高速公路。MT缺陷的性质，其故障的机械原因和神经元生理学的下游后果知之甚少，需要确定这些过程是否与大脑老化有关并与之汇合，从而提供双重有益的理解。在这里，我们提供了新的机会来解决这些问题，使用一个新建立的模型，轻度重复性创伤的果蝇。果蝇是最强大的遗传模型之一：它具有时间和成本效益，并且非常适合实验。使用这个模型，我们观察到，重复的轻度创伤诱导过早老化的功能，我们熟悉我们的老化研究。特征包括轴突肿胀和突触衰退、MT的分解以及线粒体和自噬体的变化。在此，我们将利用这一模型来证明两个假设：（a）轴突MT束损伤是创伤的主要损伤部位;我们将研究触发MT断裂的机制，以及对细胞器、细胞内运输和关键神经元功能退化的连锁效应;（B）创伤导致过早衰老;我们将研究创伤是否影响与衰老相似的神经元成分和过程，并使用延迟衰老的干预措施来观察这些干预措施是否改善创伤的长期影响。2我们的项目包括四个主要目标。(1)我们将建立创伤和衰老的细胞生物学之间的共性。(2)我们将专注于创伤和衰老所共有的MT分解，并确定所涉及的过程和蛋白质，它们的功能如何受到创伤的影响，以及它们的积极操纵是否可以改善创伤病理学。(3)我们将评估MT分解对神经元生理学的影响，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操作是否可以改善病理畸变。(4)我们将通过积极操纵衰老和长寿信号通路的细胞应激源来研究创伤和衰老的共同机制，看看它们是否能改善创伤病理学，就像它们在衰老中所做的那样。基于调节神经元细胞骨架的分子和机制的高度进化保守性，细胞器生物学，对脑创伤和衰老过程的反应，我们期望从我们的工作中得出的结果将提供在临床环境中有用的重要理解。

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