FATal Effect: Investigating causative agents of TDP-43 palmitoylation and mislocalization in ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. ALS is highly heterogeneous and has no known singular cause. Of the more than 40 genes associated with ALS, TARDBP stands out, as the encoded protein TDP-43 is known to accumulate in 97% of all ALS cases, regardless of etiology. In these cases, TDP-43 mislocalizes from the nucleus to the cytoplasm resulting in a toxic loss of its native function as an RNA/DNA binding protein, and a toxic gain of cytoplasm accumulation. In neurodegenerative diseases, like ALS, protein aggregation is the most common pathological hallmark. Protein aggregation is often preceded by mislocalization and is an indicator of underlying proteostasis deficiencies. Palmitoylation, the post-translational addition of the 16-carbon fatty acid palmitate, is a reversible lipid modification that, among many things, directs protein membrane trafficking. Palmitoylation is facilitated through the actions of palmitoyl transferases (PATs). Dysregulation of palmitoylation has been linked to proteostasis deficiencies in numerous neurodegenerative diseases, including ALS. Consequently, TDP-43 mislocalization in ALS may be caused by aberrant palmitoylation. This project aims to characterize how TDP-43 localization and palmitoylation are regulated by PATS within the context of ALS. This study confirms that TDP-43 and ALS linked proteins are palmitoylated, and that mutations in TDP-43 result in altered palmitoylation. Understanding how palmitoylation of TDP-43 impacts cellular stress response and recovery within a variety of models will be integral to identifying targets for rescuing proteostasis deficiencies in neurodegenerative disease.