Altering TDP-43 domains to understand its toxic co-pathology with tau and to better model its gain-of-function roles in neurodegenerative disease

Abstract

While predominantly nuclear localized in healthy cells, in neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. TDP-43 aggregates can also be a co-pathology, associating with more severe clinical outcomes in Alzheimer’s disease (AD). In chapter 1 we generated new C. elegans models with inactivating mutations in the nuclear localization sequence (NLS) of human TDP-43, uncovering distinct cellular responses to nuclear versus cytoplasmic TDP-43 localization. In chapter 2 we use point mutations to alter TDP-43 domains in a gain of function C. elegans model to better understand its neurotoxic synergy with tau. We generated and characterized mutant TDP-43; tau transgenic lines, finding TDP-43 post translational modifications and cellular location contribute to neurotoxic synergy with tau. In chapter 3 we characterize an 18 month old cohort of a new TDP-43; tau transgenic mouse model. We found modest neurotoxic synergy between TDP-43 and tau in behavioral tests and some sex differences. These 3 chapters improve current models for studying TDP-43 in C. elegans and mice with the hopes that the cytoplasmic TDP-43 models and TDP-43; tau models will lead to biological targets and translational experiments.