Title: Does brain trauma cause premature ageing of the nervous system?
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Mild head trauma can lead to long-term post-traumatic processes that resemble cognitive decline during ageing. This suggests that trauma may accelerate ageing and share common patho-mechanisms. However, there is an incomplete understanding of the cell biological mechanisms that cause post-traumatic brain deterioration. Here we will research the cell biological processes induced by mild trauma and compare them to the ageing brain. We will use our newly established in vivo model of mild repetitive trauma in Drosophila, which allows subcellular studies of identified cells and can be combined with our ongoing ageing studies._x000D__x000D_ _x000D__x000D_ Capitalising on the powerful genetic approaches and quantifiable readouts provided by this model, we observe that trauma prematurely induces phenotypes well known to us from our work on the ageing brain. This includes the atrophy of axons and synapses, alterations of the microtubule cytoskeleton and changes in the distribution and morphology of organelles. We hypothesise that mild trauma causes later-onset organelle and axonal damage, initially triggered by axonal microtubule deregulation causing transport defects and, in turn, detrimental organelle dysfunction. This cascade of patho-mechanisms appears to be shared by trauma and ageing. We will study the mechanisms linking trauma to microtubule aberration, the knock-on effects on organelles and neuronal physiology, and stablish cytoskeletal manipulations as neuroprotective strategies. We will establish commonalities between the cell biology of trauma and ageing. We will use interventions known to delay ageing and test whether these improve trauma pathology. Throughout, we will use a combination of genetics, biochemistry, immunohistochemistry, proteomics and in vivo imaging. We expect the outcomes derived from our work to provide important understanding applicable in translational research, with implications also for research into ageing._x000D__x000D_

Lay abstract: 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. _x000D__x000D_ _x000D__x000D_ 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. _x000D__x000D_ _x000D__x000D_ 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._x000D__x000D_ _x000D__x000D_ 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._x000D__x000D_ _x000D__x000D_ 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._x000D__x000D_

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL