# STUDY ON NEURODEGENERATION USING TDP-43 TRANSGENIC RATS

> **NIH NIH R01** · FLORIDA INTERNATIONAL UNIVERSITY · 2020 · $314,775

## Abstract

   
DESCRIPTION (provided by applicant): Among known ALS genes, TDP-43 is of particular interest because its protein is hyper-phosphorylated and ubiquitinated in sporadic ALS. Compared with genetic mutation, post-translational modification is difficult to detect in patients and hard to reproduce in animal models. Therefore, a critical step toward understanding TDP-43 pathogenesis is revealing the pathways by which mutant TDP-43 causes neurodegeneration in ALS. TDP-43 binds to many RNAs and proteins, but how pathogenic mutation impacts TDP-43 function has not yet been determined, particularly in an appropriate animal model. Unexpectedly, overexpression of both WT and mutant TDP-43 in rodents causes indistinguishable phenotypes, indicating that excessive TDP-43 is neurotoxic. Because transgene expression is heavily influenced by position effect, the patterns and levels of transgene expression vary greatly from line to line. Whether mutant TDP-43 is more or less toxic than its WT form thus cannot be determined using existing transgenic models. The question regarding the impact of pathogenic mutation on TDP-43 function is further confounded by observations that TDP-43 depletion induces neurodegeneration in TDP-43 knock-out and knock-down mice. As TDP-43 binds to the 3'-untranslated region of its own mRNA and thereby regulates its own expression, the cDNA knock-in (KI) approach destroys TDP-43 self-regulatory machinery, rendering TDP-43 KI animals not very useful. Even 7 years after the discovery of TDP-43 mutation in ALS, whether mutant TDP-43 causes ALS through a gain or loss of function is still uncertain, and this unresolved issue is a roadblock to unraveling TDP-43 disease mechanisms. To resolve this critical issue, we created KI rats by introducing a single disease-linked point mutation into the rat genome. With the unprecedented rat models, we will determine how pathogenic mutation impacts TDP-43 function in a systematic manner.

## Key facts

- **NIH application ID:** 10198111
- **Project number:** 7R01NS073829-11
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** hongxia zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $314,775
- **Award type:** 7
- **Project period:** 2020-06-19 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198111

## Citation

> US National Institutes of Health, RePORTER application 10198111, STUDY ON NEURODEGENERATION USING TDP-43 TRANSGENIC RATS (7R01NS073829-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10198111. Licensed CC0.

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