Investigating the role of traumatic injury in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD)

项目总结 肌萎缩侧索硬化症和额颞叶痴呆(ALS/FTD)和相关痴呆是毁灭性的 人类神经退行性疾病具有重叠的临床和病理特征。大多数人 ALS/FTD(90-95%)病例是散发性的，只有一小部分(5-10%)病例是家族性的。几个外在因素 与ALS/FTD相关的因素包括暴露于BMAA、铅、烟草和 创伤性脑损伤(TBI)。流行病学研究表明ALS/FTD和相关的 足球运动员、拳击手、足球运动员和退伍军人中的痴呆症发病率 重复的TBI。然而，TBI在ALS/FTD发病中的分子机制和贡献如下 仍然未知。大约45%的FTD病例、95%的ALS病例和85%的TBI患者显示TDP-43病理， 而100%的阿尔茨海默病(AD)和80%的脑外伤患者有Tau病理改变。事实上，TDP-43呈阳性 细胞质内含物被证明可以预测认知功能的下降，这表明TDP-43 蛋白质是大多数ALS/FTD的病理标志物。 我们开发并发表了一种脑外伤飞行模型，以解决脑损伤和ALS/FTD的临床相关性。这个 颅脑损伤模型显示病理(TDP-43、应激颗粒(SGS)、p62和泛素)和症状(运动和 学习/记忆缺陷)，这是神经退行性疾病的特征。蛋白质组学分析确定 创伤反应的几个独特途径的改变，如核孔复合体(NPC)， 它调节核质转运(NCT)。我们在果蝇身上验证了这些蛋白质的一个子集， 啮齿动物和CTE死后脑组织。NCT蛋白质验证包括核孔素。病理性的 已知突变会导致ALS/FTD的NCT功能障碍，但TBI如何导致NCT缺陷尚不清楚 以及它对创伤条件下的病理和症状的贡献。这项建议旨在 将果蝇、啮齿动物、ipscs和身体组织结合起来，实现三个主要目标： 1.目标1(指导阶段)：确定TBI介导鼻咽癌蛋白改变和 核质运输缺陷 2.目标2(独立期)：确定NPC蛋白O-GlcN酰化在TDP-43调控中的作用 病理学和毒性 3.目标3(独立阶段)：描绘核质内转录图谱的变化 创伤性损伤中的隔室。 这些拟议的研究将促使人们深入了解脑损伤和多发性硬化之间的病理生理机制。 ALS/FTD的流行病理。

PROJECT SUMMARY Amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and related dementias are devastating human neurodegenerative diseases that share overlapping clinical and pathological features. The majority of ALS/FTD (90-95%) cases are sporadic, and only a small subset (5-10%) of cases are familial. Several extrinsic factors are linked with ALS/FTD and related, including exposure to toxins like BMAA, lead, tobacco, and traumatic brain injury (TBI). Epidemiological studies suggest significantly higher ALS/FTD and related dementia incidences among football players, boxers, soccer players, and war veterans that experience repeated TBI. However, the molecular mechanisms and the contribution of TBI in ALS/FTD pathogenesis are still unknown. About 45% of FTD cases, 95% of ALS cases, and 85 % TBI patients show TDP-43 pathology, while 100% Alzheimer’s disease (AD) and 80% TBI cases have Tau pathology. In fact, TDP-43 positive cytoplasmic inclusions have been shown to predict a decline in cognitive functions suggesting that TDP-43 protein is a pathological marker for a majority of ALS/FTD. We developed and published a TBI fly model to address brain injury and ALS/FTD's clinical association. The TBI model showed pathology (TDP-43, stress granules (SGs), p62, and ubiquitin) and symptoms (motor and learn/memory defects) that are hallmarks of neurodegenerative diseases. Proteomics analysis identified alteration in several unique pathways in response to traumatic injury, such as the nuclear pore complex (NPC), which regulates nucleocytoplasmic transport (NCT). We validated a subset of these proteins in Drosophila, rodent, and CTE postmortem brain tissues. NCT protein validations include nucleoporins. Pathological mutations are known to cause NCT dysfunction in ALS/FTD, but it is unknown how TBI leads to NCT defects and its contribution to pathologies and symptoms in traumatic injury conditions. This proposal seeks to combine Drosophila, rodent, iPSCs and postmortem tissue to accomplish 3 main goals: 1. Aim 1 (Mentored Phase): Determine the mechanism by which TBI mediates NPC protein alteration and nucleocytoplasmic transport defects 2. Aim 2 (Independent Phase): Define the role of NPC protein O-GlcNAcylation in the regulation of TDP-43 pathology and toxicity 3. Aim 3 (Independent Phase): Delineate the transcriptomic landscape changes in the nucleocytoplasmic compartment in traumatic injury. These proposed studies will precipitate insight into the pathophysiologic mechanisms linking TBI and the most prevalent pathologies in ALS/FTD.