Does brain trauma cause premature ageing of the nervous system?

人们提出了不同的环境因素来解释个体水平上大脑衰老的差异。对头部的严重到中度或反复的轻度影响现在被认为是导致大脑加速老化和痴呆的最高环境风险因素。在某些运动中反复发生的轻微头部创伤，引发一系列事件，长期影响脑组织的广泛区域，并促进神经变性，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显著特征是轴突损伤。轴突是神经元的细长突起，构成了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，数学模型研究和体外拉伸实验表明。轴突mt排列成平行束，(a)形成结构骨干，防止机械应力；(b)作为维持生命的物质和细胞器轴突运输的高速公路进出细胞体。MT缺陷的性质，其破坏的机制原因以及对神经元生理的下游后果知之甚少，需要确定这些过程是否与大脑衰老相关并与之收敛，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，使用果蝇轻度重复性创伤的新建立的模型。果蝇是最强大的基因模型之一：它既省时又划算，而且特别适合实验。使用这个模型，我们观察到反复的轻度创伤会诱发衰老的过早特征，这是我们在衰老研究中所熟悉的。其特征包括轴突肿胀、突触衰退、线粒体和自噬体的改变。在这里，我们将利用这个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MTs分解的机制，以及对细胞器、细胞内运输和关键神经元功能恶化的连锁效应；(b)创伤导致过早衰老；我们将研究创伤是否会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会改善创伤的长期影响。我们的项目涉及四个关键目标。(1)我们将建立创伤和衰老细胞生物学之间的共性。(2)我们将重点关注创伤和衰老共同导致的MT破坏，并确定相关的过程和蛋白质，它们的功能如何受到创伤的影响，以及它们的积极操作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手法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。基于分子的高度进化守恒和调节神经元细胞骨架、细胞器生物学、对脑创伤和衰老过程的反应的机制，我们期望从我们的工作中得到的结果将提供一个重要的理解，可以在临床环境中有用。

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.