Matrin3 Misfolding in Amyotrophic Lateral Sclerosis
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by degeneration of upper and lower motor neurons in the brain and the spinal cord, respectively. ALS is associated with protein misfolding and inclusion formation of several RNA binding proteins, such as TAR DNA binding protein (TDP-43) and Fused in Sarcoma (FUS). Matrin3 is a nuclear DNA and RNA binding protein and mutations in the gene encoding Matrin3 have been identified as a cause of familial ALS (fALS). Matrin3 is an intrinsically disordered RNA binding protein with numerous phosphorylation sites. This study attempts to understand the role of the intrinsically disordered regions and protein phosphorylation on Matrin3 misfolding and mis-localization using a novel yeast model, mammalian neuronal cells, and post-mortem human neuronal tissue from the spinal cords of ALS patients. We propose that the intrinsically amino terminal disordered region and protein phosphorylation drive Matrin3 misfolding in ALS.