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...