Modeling ALS-associated Matrin-3 toxicity in yeast

Widad El-Zein, Wright State University


ALS is a neurodegenerative disease characterized by degeneration of upper and lower motor neurons in the brain and spinal cord leading to progressive paralysis and ultimately death. Perturbations in RNA metabolism and RNA binding proteins have emerged as underlying defects in ALS pathogenesis. Matrin-3 is a multifunctional RNA binding protein that has been linked to familial and sporadic ALS. Matrin-3 is normally found in the nucleus, but mutations in the gene cause mislocalization of the protein from the nucleus into the cytoplasm of neuronal cells where it forms protein aggregates. In this study, we show that over-expressing human MATR3 in the budding yeast, Saccharomyces cerevisiae, results in cellular toxicity and cytoplasmic aggregation, recapitulating phenotypes of mutant Matrin-3 in mammalian models and patients. We tested Matrin-3 with other ALS-associated RBPs and identified human genes that rescue cells from Matrin-3-induced growth defects without altering protein aggregation patterns.