Stress Granule Dysregulation in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no current cure. ALS causes degeneration of both upper and lower motor neurons leading to atrophy of the innervating muscles and progressive paralysis. The exact mechanism of the pathology of ALS is unknown. However, 147 genes have been identified that are causative, associated with, or modify disease progression. While the causative mechanism is unknown, a number of pathological processes have been associated with ALS. These include mitochondrial dysfunction, protein accumulation, and defects in RNA metabolism. RNA metabolism is a complicated process that is regulated by many different RNA-binding proteins (RBPs). A small defect in RNA metabolism can produce results as dramatic as determining cell survival. Stress granules (SGs) control RNA translation during stressed conditions. This is a protective reaction, but in conditions of chronic stress can become pathogenic. SGs are even hypothesized to act as a seeding mechanism for the pathological aggregation of proteins seen in many neurodegenerative diseases, including TAR DNA-binding protein 43 (TDP-43) in ALS. In this review, we will be summarizing the current findings of SG pathology in ALS. We also focus on the role of SG dysregulation in protein aggregate formation and mitochondrial dysfunction. In addition, we outline therapeutic strategies that target SG components in ALS.