# Effects of TDP-43 Proteinopathy on Retrotransposon Activation and Cell-Type Specific Vulnerability in a Mammalian Model of Alzheimer's and Related Dementias

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $536,013

## Abstract

PROJECT ABSTRACT:
This proposal will test key aspects of the roles of TDP-43 proteinopathy and endogenous
retroviruses in the pathology of amyotrophic lateral sclerosis/frontotemporal dementia and
Alzheimer’s and related dementias. This proposal will test, in a mammalian model, the hypothesis
that reactivation of retrotransposons (RTEs) is a means for neurodegeneration and dementia
through the following actions: (1) TDP-43 toxicity causes RTE activation in neurons and glia, (2)
the effects of TDP-43 on RTEs are non-cell autonomous, and (3) RTEs contribute to toxicity and
non-cell autonomy. This proposal will also establish a first-ever mammalian platform to investigate
TDP- 43 and RTEs in an established neurodegeneration/dementia model, the TDP-43-Q331K
mutant mouse. Two complementary approaches will be used to investigate the role of TDP-43 in
retrotransposon biology. First, a low-expressing Tg-hTDP-43-Q331K, but not a low-expressing
Tg-hTPD43-WT model, develops motor dysfunction and loss of spinal motor neurons. Second,
high overexpression of TDP-43 in either neurons or astrocytes through localized AAV brain
injections provides the means to investigate non-cell autonomous signaling between neurons and
glia. By driving overexpression only in neurons or glia with AAV virus, the effects of TDP-43
pathology on RTE expression will also be determined, and the non-cell autonomous spread of
toxic effects between these cell types. Finally, the relationship of soluble oligomerization to the
disease phenotypes will be determined, allowing the pursuit of additional translational
investigations into the potential use of reverse transcriptase inhibitors and disaggregase
compounds for alleviating or delaying progression of disease.

## Key facts

- **NIH application ID:** 10745922
- **Project number:** 5R01AG079898-02
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** ROGER B SHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,013
- **Award type:** 5
- **Project period:** 2022-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745922

## Citation

> US National Institutes of Health, RePORTER application 10745922, Effects of TDP-43 Proteinopathy on Retrotransposon Activation and Cell-Type Specific Vulnerability in a Mammalian Model of Alzheimer's and Related Dementias (5R01AG079898-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10745922. Licensed CC0.

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