# Role of oligomeric TDP-43 aggregate intermediates in ALS and frontotemporal dementia

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2022 · $379,932

## Abstract

The goal of this grant is to elucidate key mechanisms of TDP-43 aggregation by uncovering how this process
leads to pathology and neurotoxicity. TDP-43 aggregation is the pathological hallmark of amyotrophic lateral
sclerosis (ALS) and half of frontotemporal dementia (FTD) cases. In addition, TDP-43 lesions are a secondary
pathology in approximately 50% of Alzheimer's disease. A major goal in combatting ALS and FTD has been to
reduce the accumulation of TDP-43 inclusions by developing strategies to prevent or reverse TDP-43
aggregation. Recognizing this, we established strategic methods to study the aggregation of this RNA binding
protein using purified TDP-43 and have identified previously unknown aggregate intermediates. These are
early stage oligomers that share key characteristics with toxic oligomeric species of well-studied proteins linked
to neurodegeneration, including Tau, amyloid-β and α-synuclein. These TDP-43 aggregate intermediates are
capable of seeding de novo intracellular TDP-43 aggregation and their formation is accelerated by ALS-linked
mutations. Our recent findings provide the unique opportunity to shed light on fundamental mechanisms of
TDP-43 aggregation, determine their role in pathogenesis and provide models to block TDP-43 pathology. Aim
1 will establish the presence of TDP-43 oligomers in cellular models of aggregation and in ALS and FTD-
derived tissue. In particular, we will examine recruitment of the intermediates to cytoplasmic stress granules,
which are protein-RNA rich bodies considered to be crucibles of pathological aggregation. This will be
achieved using our established methods of detection and by developing antibodies specific for the intermediate
complexes. To establish the role of the newly found TDP-43 intermediates in aggregation and pathogenesis,
Aim 2 will define the molecular determinants of assembly and test how disease-associated conditions
upregulate this process. After identifying the protein regions mediating oligomerization, we will ask whether
aggregation and intracellular seeding function decrease upon disruption of the newly identified epitopes. The
ability of TDP-43 aggregates to act as agents of pathological spread in disease is strongly suggested by recent
findings that FTD-derived extracts seed and propagate TDP-43 pathology in mouse brain. Aim 3 will test
whether TDP-43 aggregates alone can indeed initiate de novo aggregation and propagation of pathology in
vivo. We will analyze the spread of TDP-43 pathology upon injection of early and late stage TDP-43
aggregates derived from purified protein in the brain of mice. This will establish whether TDP-43 aggregates,
and TDP-43 oligomers in particular, are primary sources of nucleation and neurotoxicity. Furthermore, these
studies we will determine whether this propagation directly correlates with increased neurodegeneration. With
the successful completion of this grant, we will: a) define fundamental processes in TDP-43 aggregation; b)
establ...

## Key facts

- **NIH application ID:** 10335751
- **Project number:** 5R01NS114289-03
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Yuna Ayala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $379,932
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335751

## Citation

> US National Institutes of Health, RePORTER application 10335751, Role of oligomeric TDP-43 aggregate intermediates in ALS and frontotemporal dementia (5R01NS114289-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10335751. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*