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.

PROJECT NARRATIVE Traumatic brain injury (TBI) patients displaying a wide range of neurological symptoms are at a greater risk to develop neurodegenerative diseases such as ALS/FTD, and AD and other- related dementia (ADRD). This proposal seeks to explore how TBI leads to symptoms and pathologies seen in neurological diseases such as ALS/FTD. Understanding the mechanism of TBI-mediated neurodegeneration will be instrumental in developing novel therapeutic approaches.