# Evaluating Protein Quality Control in the Toxicity of TDP43 Fragments Associated with ALS and FTD

> **NIH NIH R15** · TEXAS WOMAN'S UNIVERSITY · 2021 · $385,343

## Abstract

Project Summary
People are living longer, which increases their risk of developing neurodegenerative disorders. Such
disorders can be characterized by the accumulation and aggregation of specific proteins in the brain.
These aggregates often contain protein fragments produced by increases in protein cleavage or
defects in protein quality control (PQC) systems such as regulated protein degradation. We do not
know how all protein fragments are metabolized and how they cause toxicity to neurons. Our overall
goal is to understand the effects of protein aggregates on normal cell function and to identify cellular
pathways that prevent toxicity. Previously, we found that the N-degron pathway can degrade specific
C-terminal fragments (CTFs) associated with neurodegenerative disorders. We also found that the N-
termini of CTFs influence their metabolism, tendency to aggregate, and the morphology of their
aggregates. In recent work, we found that Bcl-2-associated athanogene 6 (BAG6) interacts with CTFs
linked to disease and increases their solubility. BAG6 is a component of a chaperone complex that
determines the fate of unfolded proteins. In this work, we developed new methods to examine CTFs
with natural N-termini in cultured neurons and in transgenic mouse models. Using these methods, we
will determine how BAG6 regulates the metabolism of CTFs that are prone to aggregate. We will also
establish whether aggregates of CTFs cause toxicity that leads to neurodegeneration. This project will
help us better understand how protein fragments are toxic and how cellular PQC guards against
neurodegeneration.

## Key facts

- **NIH application ID:** 10113946
- **Project number:** 2R15NS095317-02A1
- **Recipient organization:** TEXAS WOMAN'S UNIVERSITY
- **Principal Investigator:** Christopher Scott Brower
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,343
- **Award type:** 2
- **Project period:** 2016-05-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113946

## Citation

> US National Institutes of Health, RePORTER application 10113946, Evaluating Protein Quality Control in the Toxicity of TDP43 Fragments Associated with ALS and FTD (2R15NS095317-02A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10113946. Licensed CC0.

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