# Examining cross-species suppression of neurodegeneration by loss of a conserved RNA binding protein in models of ALS and FTD

> **NIH NIH R21** · BROWN UNIVERSITY · 2021 · $416,481

## Abstract

Etiological mechanisms for Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are
poorly defined, but mutations in multiple genes can cause FTD, ALS, or a mixed clinical syndrome. This
suggests that common molecular pathways underlie disease pathogenesis. Phenotype-based genetic studies
in model organisms are a powerful strategy for identifying these pathogenic mechanisms and potential
therapeutic targets. Here, we focus on a conserved RNA-binding protein, which suppresses pathology in a
genetic model for ALS in C. elegans. We propose to initiate analysis of the mechanism of suppression and to
test for beneficial effects in additional FTD/ALS models in both C. elegans and mice.
Historically, work in the FTD/ALS field has relied on animal models that mis- or over-express disease proteins.
However, disease proteins are not over-expressed in patients, over-expression of wild-type protein is often
toxic, and disentangling disease mechanisms from artificial effects of mis-/over-expression is therefore
challenging. Instead, we primarily rely on knock-in models, created by directly editing the endogenous genes to
insert patient amino acid changes. In our C. elegans knock-in model for sod-1G85R, we observe
stress-induced degeneration of cholinergic and glutamatergic neurons, but not loss of dopaminergic or
serotonergic neurons. A similar approach was used to develop the mouse knock-in mouse model for
Sod1G85R, which exhibits progressive motor neuron degeneration. We undertook the first genetic suppressor
screen using a knock-in animal model and identified an RNA-binding protein whose loss of function
suppresses both glutamatergic and cholinergic neurodegeneration in knock-in sod-1G85R C. elegans.
Intriguingly, a vertebrate ortholog of this RNA-binding protein is found in RNA/protein granules in axonal
processes, along with HNRNPA1, FUS, and other proteins whose mutation causes FTD/ALS, and was
identified as a suppressor of C9orf72-associated dipeptide repeat-induced toxicity.
Understanding how loss of this RNA binding protein suppresses neurodegeneration may provide insights into
why mutation of SOD1, HNRNPA1, FUS, or other proteins leads to FTD/ALS. In our first aim, we plan to
identify the mechanism of suppression in C. elegans and examine the ability of this suppressor to decrease
degeneration in other models of FTD/ALS (C9orf72, HNRNPA1, FUS, and TDP43). Further, it is important to
determine whether loss of this RNA binding protein can also suppress degeneration in vertebrate models. In
the second aim, we assess conservation of suppression in the murine SOD1G85R knock-in model. Combined,
these aims will provide insight into pathogenic mechanisms, may link SOD1-associated ALS to FTD/ALS
caused by mutation of other RNA-binding proteins (e.g. FUS), and will help determine if future in-depth studies
in vertebrate models are warranted to develop therapeutic interventions that target the RNA-binding protein
encoded by this suppressor gen...

## Key facts

- **NIH application ID:** 10195707
- **Project number:** 1R21NS121977-01
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Anne Church Hart
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $416,481
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195707

## Citation

> US National Institutes of Health, RePORTER application 10195707, Examining cross-species suppression of neurodegeneration by loss of a conserved RNA binding protein in models of ALS and FTD (1R21NS121977-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10195707. Licensed CC0.

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