Senior Capstone Experience by Cole Craig Rineer ’19

Submitted to the Department of Biology

Advised by Dr. Mala Misra

Abstract: “Rapid progress has been made in identifying genetic underpinnings associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). In the past few years, there has been significant agreement of the idea of heterogeneous nuclear ribonucleoproteins (hnRNPs) and the proteins which make them up, are central drivers in the pathobiology of ALS (Purice & Taylor, 2018). ALS has no known etiology and is a rapid, fatal neurodegenerative disease characterized by pathological inclusions within motor and cortical neurons, predominantly consisting of TAR DNA-binding protein 43 kDa (TDP-43) (Khalfallah et al., 2018). This protein mediates liquid-liquid phase separation (LLPS) in formation and decomposition of stress granules (SGs), which act as a first line defense mechanism in response to cellular stress (Aulas et al., 2017). SGs are membraneless, highly interactive with cytoplasmic material, and function to sequester expression of unwanted mRNAs during times of cellular stress, allowing the cell to recover (Purice & Taylor, 2018). It is believed that TDP-43 may serve as the interface between environmental stress and genetic susceptibility, by causing SGs to turn pathological, acting as the “seed” of neuronal inclusions (Aulas & Vande Velde, 2015; Mateju et al., 2017). Cells have protein quality control (PQC) machinery and chaperones to maintain healthy SGs, but age, mutations, and chronic stress exposure may overwhelm these processes (Purice & Taylor, 2018). This review aims to add clarity to how SGs turn pathological, but future research is necessary to gain a better understanding of the mechanisms involved. “

Read Cole’s SCE below: