# Connecting TDP-43 Pathology to the Molecular Profiles of Neurodegeneration

> **NIH NIH RF1** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $1,118,091

## Abstract

PROJECT SUMMARY
It has become increasingly clear that TDP-43 pathology is associated with a range of neurodegenerative
disorders. Great strides have been made to understand the impact of TDP- 43 in ALS and FTD-TDP, two
diseases where TDP-43 pathology is a hallmark of disease. Yet, the mechanism(s) by which TDP-43 contributes
to neurotoxicity are still not fully understood for any TDP-43 associated disorder. We recently published results
from the NYGC ALS Consortium, a large patient profiling study that included whole genome sequencing, deep
transcriptome sequencing, and high resolution IHC tissue staining for patients with ALS and FTD. The major
finding of this study was that ALS and FTD patients could be grouped into three distinct and robust molecular
subtypes, based upon their transcriptome profiles and subsequent IHC validation of key proteins tied to these
subtypes. We demonstrated that TDP-43 pathology was most strongly associated with de-silencing of
retrotransposons, viral-like elements that are normally silent in most adult tissues. Retrotransposons have been
shown to be both neuroinflammatory and neurotoxic in other disease contexts, suggesting a possible contributing
mechanism for TDP-43 mediated neurotoxicity. Yet the hypothesis that retrotransposons contribute to TDP-43
mediated cellular toxicity remains untested. This proposal will conclusively test the degree to which
retrotransposons contribute to TDP-43 associated toxicity, and the mechanism by which this occurs.
Aim 1: How does the cell- and tissue-specific context of TDP-43 pathology affect its impact? We will use
multiplexed IHC staining for TDP-43 pathology combined with spatially resolved transcriptomics to conclusively
determine which genes and retrotransposons show alterations in cells with TDP-43 pathology in frontal cortex
samples from patients with TDP-43 associated common dementias.
Aim 2: Do active retrotransposons simply report on TDP-43 pathology or contribute to cellular toxicity?
We will test for the ability of TDP-43 dependent retrotransposons to contribute to cellular toxicity in cells with
TDP-43 pathology, i.e. cell intrinsic mechanisms.
Aim 3: Can TDP-43 dependent retrotransposons contribute to activation of astrocytes and microglia?
We will test for the ability of TDP-43 dependent retrotransposons to contribute to activation of adjacent astrocytes
and microglia, i.e. cell non-autonomous mechanisms.

## Key facts

- **NIH application ID:** 10934068
- **Project number:** 7RF1NS118570-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Molly Gale Hammell
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,118,091
- **Award type:** 7
- **Project period:** 2020-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934068

## Citation

> US National Institutes of Health, RePORTER application 10934068, Connecting TDP-43 Pathology to the Molecular Profiles of Neurodegeneration (7RF1NS118570-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10934068. Licensed CC0.

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