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.

TAR DNA binding protein 43 (TDP-43) A315T mutation (TDP-43(A315T)) 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-43(A315T) enhanced neuronal toxicity via activating endoplasmic reticulum (ER) stress-mediated apoptosis in SH-SY5Y cells. Moreover, autophagy was activated by overexpression of TDP-43(A315T) in a self-defensive manner to decrease neuronal toxicity. Inhibition of autophagy attenuates TDP-43(A315T) 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-43(A315T) mutation were markedly higher than those from the healthy control. Thus, our findings provide new molecular evidence for TDP-43(A315T) neuropathology. In addition, the pathological change in the skin tissues of the patients with TDP-43(A315T) mutation can be used as a quick diagnostic biomarker.