Abstract

Introduction: TDP43 is a nuclear protein involved in crucial functions related to RNA metabolism. TDP43 has been described as the major component of the pathologic inclusions present in post-mortem tissues of most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we described and characterized the presence of TDP43 aggregates in tissue extracts from a transgenic mouse model that overexpresses a mutant form of TDP43 (A315T) in the central nervous system. We also studied endoplasmic reticulum (ER) stress responses in cellular and animal models. We hypothesized that misfolded species could be altering the ER proteostasis in affected cells. Methods: Protein aggregation was analyzed by western blot and filter trap and activation of Unfolded Protein Response (UPR) by qPCR. Histological analysis of cortex and spinal cord from transgenic animals (TDP43A315T) were performed in a symptomatic stage and non-transgenic controls. Results: TDP43 protein aggregates, in non-reducing conditions, and ubiquitinated inclusions were detected in cortex and spinal cord of TDP43A315T in symptomatic mice. Unexpectedly, decreased levels of UPR markers were found in TDP43A315T mice. We also found that ER stress responses are impaired in mouse and cellular models expressing mutant forms of TDP43 under ER stress conditions. Discussion: These data shows that mutant forms of TDP43 could be involved in the insensibility of mutant TDP43 systems to respond under ER or other stress conditions.