# Effects of TDP-43 Pathology on Innate Antiviral Mechanisms in Neurodegenerative Disease

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $46,752

## Abstract

Project Summary/Abstract
Dysregulation of transactivating response region DNA-binding protein-43 (TDP-43) has been linked to many
neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer’s
disease (AD). TDP-43 has a variety of functions linked to its RNA-binding motif, including regulation of
transcription, splicing, and RNA transport. Along with these effects, TDP-43 alters expression of interferon (IFN)-
related and other immune genes essential for antiviral responses. The relationship between viral pathogens and
TDP-43 is bidirectional, as exposure to poly(I:C), which simulates viral pathogens, can promote subcellular
mislocalization of TDP-43. Viral pathogens, like TDP-43 dysregulation, are linked to AD and other dementias;
AD has been associated with increased presence of viral pathogens, like herpes simplex virus 1 (HSV-1), and
altered IFN-related signaling and neuroimmune cascades. Our laboratory found that, like neuronal TDP-43,
astrocytic TDP-43 can be mislocalized to the cytoplasm in AD. Dysregulation of astrocytic TDP-43 in mouse
models caused neural deficits and cell-autonomous changes in antiviral and IFN-inducible factors. Further,
dysregulated TDP-43 increased astrocytic susceptibility to HSV-1. Astrocytic susceptibility to HSV-1 associated
with overexpression of human TDP-43 was reduced by blocking the ability of human TDP-43 to bind RNA.
Previous studies also show that the RNA-binding domain on TDP-43 is necessary for its other disease-linked
effects. Based on this evidence, I will test the hypothesis that dementia-related TDP-43 dysfunction affects
antiviral pathways and increases neural susceptibility to HSV-1 by altering TDP-43 binding to host RNA, resulting
in aberrant host antiviral and immune gene expression and impaired innate antiviral signaling. I propose to use
a variety of cellular and molecular techniques to examine in vitro (Aim 1.1) and in vivo (Aim 1.2) susceptibility to
HSV-1 following cell-specific expression of TDP-43 variants that either maintain nuclear localization, mislocalize
to the cytoplasm, cannot bind to RNA, or both. I will also determine cell-specific molecular mechanisms that
promote differences in antiviral pathways via single-cell RNA sequencing (Aim 2.1), and conduct targeted
analysis of alternative splicing (ScISOr-Seq), transposable element expression (TEtranscripts), and protein
levels (Western blotting). Finally, I will examine the physiological functions of differential genes of interest
identified in Aim 2.1 using genetic and pharmacological approaches. Uncovering the mechanistic links that
connect TDP-43 dysregulation to antiviral pathways and viral susceptibility may define new pathobiological
mechanisms and therapeutic targets to prevent neurodegenerative disease onset and progression.

## Key facts

- **NIH application ID:** 10537727
- **Project number:** 1F31AG079616-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Stephanie Jackvony
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537727

## Citation

> US National Institutes of Health, RePORTER application 10537727, Effects of TDP-43 Pathology on Innate Antiviral Mechanisms in Neurodegenerative Disease (1F31AG079616-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10537727. Licensed CC0.

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