# How TDP-43 nuclear depletion contributes to aberrant neural activity and ultimately neurodegeneration?

> **NIH NIH P20** · UNIVERSITY OF WYOMING · 2022 · $208,058

## Abstract

The overall objective of this proposal is using mouse models to examine the
pathogenic mechanism by which loss of TAR DNA binding protein 43kDa (TDP-43)
contributes to aberrant neural activity and, ultimately, neurodegeneration. TDP-43
predominantly functions as a nuclear protein important for transcription regulation.
However, its cytosolic aggregates are commonly found in patients with
neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and
frontotemporal dementia (FTD). Since cytosolic accumulation of TDP-43 is usually
accompanied by its nuclear clearance, a loss-of-function mechanism has been proposed
to contribute to neurodegeneration. The underlying pathogenic pathways driven by the
loss-of-function of TDP-43 are largely unknown.
 Our preliminary in vivo calcium imaging studies demonstrated biphasic changes at
population levels from pyramidal neurons of prefrontal cortex in spontaneously occurring
calcium transients following TDP-43 depletion. We propose to study the pathogenic
mechanisms of TDP-43 loss-of-function on two levels: Frist, we will repetitively measure
from the same pyramidal neurons, the spontaneously occurring calcium transients over
time, to elucidate phasic changes in neural calcium transients following TDP-43 depletion.
Second, we will measure phasic changes in intrinsic excitability of pyramidal neurons
elicited by TDP-43 depletion, to decipher the correlation between abnormalities in calcium
transients and neural excitability. Completion of the proposed studies will determine how
TDP-43 loss-of-function drives aberrant neural activity prior to neurodegeneration,
whether hyperactivity and hypoactivity are mechanistically related, and which of the two
is the primary driving force for pathogenesis. Filling these knowledge gaps will help to
pave the new way towards early intervention for ALS and FTD.

## Key facts

- **NIH application ID:** 10495798
- **Project number:** 2P20GM121310-06
- **Recipient organization:** UNIVERSITY OF WYOMING
- **Principal Investigator:** YUN LI
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $208,058
- **Award type:** 2
- **Project period:** 2017-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495798

## Citation

> US National Institutes of Health, RePORTER application 10495798, How TDP-43 nuclear depletion contributes to aberrant neural activity and ultimately neurodegeneration? (2P20GM121310-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10495798. Licensed CC0.

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