Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Anatomy and Cell Biology

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.

Summary for Lay Audience

Amyotrophic lateral sclerosis (ALS) is a fatal disease that affects a specific group of nerve cells inside our brains and spinal cords called motor neurons. Motor neurons cells that control the movement of our muscles. Scientists have discovered a link between ALS and defects in proteins. Proteins are the molecules that carry out most of the functions inside our cells. For proteins to be able to perform their function, they have to attain a specific shape through a well-regulated process called protein folding. In ALS, some proteins lose their proper shape and acquire a different one which is a process called protein misfolding. These misfolded proteins can accumulate inside the neurons, become toxic and prevent the neurons them from functioning properly. There are several factors that can regulate the process of folding, such as protein phosphorylation and intrinsically disordered regions. Protein phosphorylation is the addition of phosphate groups at specific sites in the protein to help its proper folding. There is evidence that there are changes in protein phosphorylation in ALS patients. Intrinsically disordered regions are parts in some proteins that do not have a specific shape due to their high flexibility. This flexibility helps the protein perform its function and bind to many other proteins. The downside to this flexibility is that it renders the protein prone to misfolding. Scientists have found that many of proteins misfolding in ALS have intrinsically disordered regions.

In this thesis we explore the misfolding of Matrin3, a nuclear protein that becomes abnormally altered in ALS individuals. Matrin3 has many phosphorylation sites and two large intrinsically disordered regions, so we decided to study how these factors contribute to Matrin3 misfolding in ALS. We began our studies in a yeast model, which allows us to isolate Matrin3 and test its toxicity and localization. Interestingly, we discovered that protein phosphorylation and one the intrinsically disordered regions plays a major role in Matrin3 toxicity. Thus, we speculate that altered protein phosphorylation and intrinsically disordered regions drive Matrin3 misfolding in ALS patients leading to motor neuron dysfunction.

Download

Share

COinS