Activation of ER stress and autophagy induced by TDP-43 A315T as pathogenic mechanism and the corresponding histological changes in skin as potential biomarker for ALS with the mutation

Abstract

TAR DNA binding protein 43 (TDP-43) A315T mutation (TDP-43A315T) has been found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) as a disease causing mutation with enhanced protein aggregation, formation of protease-resistant fragments, and neurotoxicity. However, the molecular mechanisms for its pathogenic effects are largely unknown. In this study, we demonstrate that TDP-43A315T enhanced neuronal toxicity via activating endoplasmic reticulum (ER) stress-mediated apoptosis in SH-SY5Y cells. Moreover, autophagy was activated by overexpression of TDP-43A315T in a self-defensive manner to decrease neuronal toxicity. Inhibition of autophagy attenuates TDP-43A315T induced neuronal cell death. Furthermore, the expression levels of TDP-43, ER chaperone 78 kDa glucose-regulated protein (GRP-78), and autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) in the skin tissues from ALS patients with TDP-43A315T mutation were markedly higher than those from the healthy control. Thus, our findings provide new molecular evidence for TDP-43A315T neuropathology. In addition, the pathological change in the skin tissues of the patients with TDP-43A315T mutation can be used as a quick diagnostic biomarker.