# Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $340,156

## Abstract

TDP-43 dysfunction underlies a spectrum of neurodegenerative diseases collectively known as TDP-43
proteinopathies, which are characterized by neuronal loss, behavioral abnormalities, and ultimately death.
Surprisingly, little is known about how TDP-43 undergoes such a dramatic transformation that initiates disease
progression. Recently, we discovered that TDP-43 is subject to reversible lysine acetylation, a modification
within TDP-43’s RNA-binding domain that has a remarkable effect; it disengages TDP-43 from its target
mRNAs and accelerates TDP-43’s propensity to aggregate. Indeed, acetylated TDP-43 inclusions were
detected in motor neurons of amyotrophic lateral sclerosis (ALS) patients, suggesting a role for this aberrantly
modified form of TDP-43 in disease pathogenesis. We leveraged this intriguing finding to generate the first
CRISPR-based, non-transgenic TDP-43 mouse model containing an acetylation-mimicking mutation, thus
producing a physiologically relevant model of TDP-43 proteinopathy. We hypothesize that TDP-43
acetylation drives neurodegeneration and disease progression, which can now be directly tested in
vivo. Our preliminary data already show evidence of TDP-43 pathology, nuclear TDP-43 clearing, and
prominent behavioral defects in mutant mice. In Aim-1, we will use histology, biochemical, and behavior
approaches to fully characterize the neurodegenerative phenotype. In Aim-2, we shed light on the therapeutic
potential of activating the master transcription factor HSF1, or specific downstream chaperones, to induce a
highly coordinated transcriptional cascade capable of suppressing acetylated TDP-43 dysfunction and
restoring nuclear TDP-43 levels. Finally, in Aim-3, we will uncover early-stage perturbations in the
transcriptome that occur in response to acetylated TDP-43, but emerge prior to overt neurodegeneration and
behavioral defects. Our proposal is significant since it will highlight an aberrant form of TDP-43 as a plausible
therapeutic target, it will pinpoint specific chaperone responses as new avenues to detoxify neurons, and it will
illuminate transcriptional dysregulation as a critical pathomechanism associated with neurodegeneration. Our
proposal is also innovative since we will shed light on aberrant TDP-43 modifications as plausible triggers for
disease onset or progression.

## Key facts

- **NIH application ID:** 10146499
- **Project number:** 5R01NS105981-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Todd Jonathan Cohen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $340,156
- **Award type:** 5
- **Project period:** 2018-06-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146499

## Citation

> US National Institutes of Health, RePORTER application 10146499, Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration (5R01NS105981-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146499. Licensed CC0.

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