# Identification of conserved ALS-FTD suppressor genes

> **NIH NIH R21** · BROWN UNIVERSITY · 2021 · $437,532

## Abstract

The molecular mechanisms that underlie pathogenesis in ALS, FTD, and related diseases are poorly
defined. But, a preponderance of evidence suggests that common mechanisms contribute to both ALS and
FTD pathogenesis. For example, C9ORF72 disease alleles can lead to ALS and/or FTD symptoms.
Additionally, TDP-43 protein cytoplasmic inclusions are seen in a large fraction of patients. Previous work has
also shown that disease genes are usually conserved across the animal kingdom. This conservation has been
repeatedly demonstrated by the successful creation of Drosophila, C. elegans and Saccharomyces models of
ALS and FTD. Additionally, the relationships between disease genes and modifier genes are conserved across
the animal species, as shown by published work and our preliminary results for UNC13. Finally, previous work
has also demonstrated that modifier gene activity is often not specific to just one disease gene; for example,
multiple ALS disease models can be affected by the same modifier gene (e.g. UNC13A and XPO1 modify in
SOD1 and other models of ALS). Because modifier genes can have dramatic impact on patient disease and
understanding these genes will shed light on pathogenic mechanisms underlying ALS, FTD, and related
diseases, we harness C. elegans genetics to identify suppressor gene families and associated pathways.
 To identify new suppressor genes, we used a C. elegans knock-in model, created by directly editing the
endogenous C. elegans sod-1 gene to insert patient amino acid changes. In the resulting knock-in model
animals, we observe stress-induced degeneration of cholinergic and glutamatergic neurons, but not loss of
dopaminergic or serotonergic neurons. In the Preliminary Results section, we describe our unbiased genetic
screen focused on suppressing glutamatergic neuron degeneration in sod-1G85R animals. This is the first full-
scale suppressor screen in a model organism that is based on a knock-in animal model. We have already
identified two genes whose loss of function suppresses degeneration. Here, we propose to identify 20 to 30
additional suppressor genes. We will examine the ability of these conserved suppressor genes to decrease
degeneration in C. elegans models of ALS and FTD caused by mutations in C9orf72, FUS, and TDP43 genes
and determine if suppressor genes decrease sod-1 expression or SOD-1 levels, which will provide mechanistic
insight into suppressor gene mechanism of action.
 While genetic screens can be considered high risk/high gain, our proposed studies are solidly grounded
in robust preliminary results, our demonstrated expertise, and our enthusiasm for collaboratively moving
suppressor genes and pathways into vertebrate models. The R21 funding mechanism is intended for “high
risk, high reward studies that may lead to a breakthrough in a particular area” which “will impact biomedical,
behavioral, or clinical research”. The proposed studies will lead to the novel discovery of modifier genes and
associated pathw...

## Key facts

- **NIH application ID:** 10127911
- **Project number:** 1R21NS116254-01A1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Anne Church Hart
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $437,532
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127911

## Citation

> US National Institutes of Health, RePORTER application 10127911, Identification of conserved ALS-FTD suppressor genes (1R21NS116254-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10127911. Licensed CC0.

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