A genetic screen for suppressors of neuron degeneration in a C. elegans sod-1G85R model of Amyotrophic Lateral Sclerosis
4 affiliations
- 1Neuroscience Department and Carney Institute for Brain Science, Brown University , Providence, Rhode Island 02912 ,
- 2Basic Sciences Division, Fred Hutchinson Cancer Center , Seattle, Washington 98109 ,
- 3School of Life and Environmental Sciences, University of Sydney , New South Wales 2006 ,
- 4Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine , Charlottesville, VA, 22908 ,
Abstract
Genetic variants in superoxide dismutase 1 (SOD1) cause the progressive neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Treatments for this disease are limited, and the unique vulnerability of cholinergic and glutamatergic motor neurons to degeneration seen in ALS patients is not clearly understood. Identifying genetic modifiers of neurodegeneration can provide insight into the selective vulnerability of motor neurons in ALS and may accelerate identification of novel therapeutic targets. Here, we describe a forward genetic screen for suppressors of the stress-induced glutamatergic neuron degeneration in a single-copy C. elegans model of sod-1G85R. Used two different screening strategies, we identified 53 suppressor lines that decreased glutamatergic neuron degeneration to varying degrees. To rapidly identify suppressor genes, we sequenced suppressor lines and identified candidate suppressor genes based on frequency of de novo exonic mutations and previously published work. Two candidates were tested and excluded as suppressor genes: erh-1 and imph-1. For a subset of unidentified suppressor lines, we determined if cholinergic neurodegeneration was also suppressed; roughly one-third of suppressor lines showed no corresponding cholinergic neuron rescue, suggesting that mechanisms involved in cholinergic and glutamatergic degeneration are at least partially divergent. This study outlines the first unbiased genetic screen in a knock-in model of SOD1 neurodegeneration, describes a cohort of candidate suppressor lines with decreased SOD1-dependent neurodegeneration, excludes two candidates and discusses approaches for suppressor mutation isolation and gene identification.
Related
- Beyond Monogenic Inheritance: Emerging Genetic Architecture of Amyotrophic Lateral Sclerosis
- Transcutaneous Carbon Dioxide Monitoring in Amyotrophic Lateral Sclerosis: A Scoping Review
- The value of a family history to distinguish monogenic from polygenic amyotrophic lateral sclerosis
- Amyotrophic Lateral Sclerosis in a Patient Treated for Neurosyphilis: A Case Report
- The prevalence of type 2 diabetes mellitus among people with amyotrophic lateral sclerosis is increasing in the United States
BibTeX
@article{yanagi2026genetic,
title = {{A genetic screen for suppressors of neuron degeneration in a C. elegans sod-1G85R model of Amyotrophic Lateral Sclerosis}},
author = {Katherine S Yanagi and Alexander T Lin-Moore and Nijpawi C Gordon and Jeremy J Lins and Emma Michaela Coyne and Kathleen L Meininger and Stephanie L Moy and Loraina A Stinson and Melissa B Walsh and Mika Gallati and Animesh Mahapatra and Ruka Aderogba and Alexander Jaworski and Anne C Hart},
journal = {G3: Genes, Genomes, Genetics},
year = {2026},
month = oct,
doi = {10.1093/g3journal/jkag281},
url = {https://academic.oup.com/g3journal/advance-article/doi/10.1093/g3journal/jkag281/8857684},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A genetic screen for suppressors of neuron degeneration in a C. elegans sod-1G85R model of Amyotrophic Lateral Sclerosis
AU - Katherine S Yanagi
AU - Alexander T Lin-Moore
AU - Nijpawi C Gordon
AU - Jeremy J Lins
AU - Emma Michaela Coyne
AU - Kathleen L Meininger
AU - Stephanie L Moy
AU - Loraina A Stinson
AU - Melissa B Walsh
AU - Mika Gallati
AU - Animesh Mahapatra
AU - Ruka Aderogba
AU - Alexander Jaworski
AU - Anne C Hart
PY - 2026
DA - 2026/10/01
JO - G3: Genes, Genomes, Genetics
DO - 10.1093/g3journal/jkag281
UR - https://academic.oup.com/g3journal/advance-article/doi/10.1093/g3journal/jkag281/8857684
AB - Genetic variants in superoxide dismutase 1 (SOD1) cause the progressive neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Treatments for this disease are limited, and the unique vulnerability of cholinergic and glutamatergic motor neurons to degeneration seen in ALS patients is not clearly understood. Identifying genetic modifiers of neurodegeneration can provide insight into the selective vulnerability of motor neurons in ALS and may accelerate identification of novel therapeutic targets. Here, we describe a forward genetic screen for suppressors of the stress-induced glutamatergic neuron degeneration in a single-copy C. elegans model of sod-1G85R. Used two different screening strategies, we identified 53 suppressor lines that decreased glutamatergic neuron degeneration to varying degrees. To rapidly identify suppressor genes, we sequenced suppressor lines and identified candidate suppressor genes based on frequency of de novo exonic mutations and previously published work. Two candidates were tested and excluded as suppressor genes: erh-1 and imph-1. For a subset of unidentified suppressor lines, we determined if cholinergic neurodegeneration was also suppressed; roughly one-third of suppressor lines showed no corresponding cholinergic neuron rescue, suggesting that mechanisms involved in cholinergic and glutamatergic degeneration are at least partially divergent. This study outlines the first unbiased genetic screen in a knock-in model of SOD1 neurodegeneration, describes a cohort of candidate suppressor lines with decreased SOD1-dependent neurodegeneration, excludes two candidates and discusses approaches for suppressor mutation isolation and gene identification.
SN - 2160-1836
ER -