Mahapatra, Animesh, Walsh, Melissa, Tsai, Jason, Hart, Anne, Lins, Jeremy, Yanagi, Katherine, Stinson, Loraina, Kruskop, Jane, Osborne, Jennifer
[
International Worm Meeting,
2021]
Amyotrophic Lateral Sclerosis (ALS) is one of the most common adult-onset neurodegenerative disorders that results from the selective and progressive degeneration of cortical and spinal motor neurons. Mutations over 20 genes including RNA binding proteins, FUS and TDP43, and a free radical scavenger, superoxide dismutase 1 (SOD1) cause ALS. Although there is a well-established genetic component of ALS, it is still unclear why mutations in genes encoding functionally diverse proteins cause motor neuron degeneration. Identifying modifiers of neurodegeneration in C. elegans ALS models may provide insight into the mechanisms behind the selective and progressive neurodegeneration in ALS. Here, we have undertaken a classical forward genetic screen to identify suppressors of glutamatergic neuron degeneration. After exposure to oxidative stress, SOD-1G85R knock-in mutants have both glutamatergic and cholinergic neuron degeneration (PMC6200258). We mutagenized SOD-1G85R animals and screened for suppressors of glutamatergic neuron degeneration. After whole genome sequencing, we found that an RNA binding protein, hit in three independently isolated lines, suppresses cholinergic and glutamatergic neuron degeneration. Understanding the relationship between SOD1 and RNA binding proteins will provide insight if there are common mechanisms underlying neurodegeneration in ALS and has the potential to facilitate the development of treatments.
[
MicroPubl Biol,
2021]
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disease. While the mechanisms underlying motor neuron death in ALS are not well understood, mutations in over 25 genes can cause this disease (Marangi and Traynor 2015). It remains unclear which, if any, of these genes act in the same disease-associated pathway(s), or if they act in the same pathway(s) as genes associated with the related disorder, frontotemporal dementia (FTD) (Ling et al. 2013). The first ALS-causing gene to be identified was superoxide dismutase 1 (SOD1), a regulator of cytoplasmic redox homeostasis (Rosen et al. 1993). We can begin to construct a pathway for neurodegeneration through SOD1 by identifying genes whose loss of function (LOF) modifies the level of degeneration in a C. elegans SOD1 ALS model. This will contribute to our understanding of whether ALS/FTD genes act in a single or multiple pathways to cause disease.