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

> **NIH NIH K99** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $125,475

## Abstract

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.

## Key facts

- **NIH application ID:** 10525629
- **Project number:** 1K99AG075363-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Eric Nathaniel Anderson
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $125,475
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525629

## Citation

> US National Institutes of Health, RePORTER application 10525629, Investigating the role of traumatic injury in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) (1K99AG075363-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10525629. Licensed CC0.

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