# 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 · $18,328

## Abstract

The overarching goal of this supplement proposal is to support a graduate student
from an underrepresented population to determine the role of TDP43 proteinopathy and
endogenous retroviruses in the pathology of amyotrophic lateral sclerosis/frontotemporal
dementia and Alzheimer’s and related dementia, using the established approaches and
strategies from the parent grant.
 In the Drosophila system, it has been established that ERVs and DNA damage play
a causal role in cell-autonomous glial cell death and in non-autonomous toxicity to nearby
neurons. Although the impacts of ERVs/RTEs have been described in Drosophila and
increased levels of ERVs/RTEs have been measured in human tissues, there are yet no tests
of this hypothesis in the initiation and progression of disease during development and aging
in a mammalian model of ALS or FTD. Here we propose essential tests of our novel
hypothesis to establish the temporal, spatial, and cell-specific impacts of TDP-43 pathology
on ERV/RTE expression and on disease progression and spread within the CNS. In addition,
we will provide a PLATFORM that will enable the field to uncover cellular mechanisms by
which RTEs/ERVs may contribute, and to do so in a vertebrate model.
 We are investigating a novel integrative in vivo experimental approach with the power
to provide insights into RTE biology, neurodegenerative phenotypes, and focal and
longitudinal perturbations in a vertebrate model of TDP-43-ALS/ADRD. The low-expressing
TDP-43 mouse strains in Aim 1 of the parent grant are mostly completed under another PhD
student, but Ariel Nieves will continue and complete these experiments. The main work for
Ariel will be to incorporate tools that we have established in our laboratory for sparse
expression (Adeno-associated viruses, AAV) in the rodent system, enabling us to manipulate
gene function in specific and focally initiated populations of cells (neurons, glia), and to
delineate effects on nearby, unperturbed cells or tissues.

## Key facts

- **NIH application ID:** 11051516
- **Project number:** 3R01AG079898-02S1
- **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:** $18,328
- **Award type:** 3
- **Project period:** 2022-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11051516

## Citation

> US National Institutes of Health, RePORTER application 11051516, Effects of TDP-43 Proteinopathy on Retrotransposon Activation and Cell-Type Specific Vulnerability in a Mammalian Model of Alzheimer's and Related Dementias (3R01AG079898-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11051516. Licensed CC0.

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