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.

RBM45 associates with nuclear stress bodies and forms nuclear inclusions during chronic cellular stress and in neurodegenerative diseases

“…As in the preceding experiments, we did not observe association of TDP-43 or FUS with NSBs ( Figure S2B). We observed that overexpression of TDP-43, but not FUS, was sufficient to promote NSB formation, consistent with previous studies showing that altered TDP-43 expression leads to cellular stress ( Figure S2B) 51,52 .…”

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

“…In addition, the TDP-43 level was higher in the skin of ALS patient with upper-limb onset compared with patients with other onsets (Abe et al, 2017). Patients with the pathological variant TDP-43(A315T) have elevated levels of TDP-43 and protein markers of ER stress (GRP-78) and autophagy (LC3) in the skin (Wang et al, 2015).…”

“…In addition, the TDP‐43 level was higher in the skin of ALS patient with upper‐limb onset compared with patients with other onsets (Abe et al., 2017). Patients with the pathological variant TDP‐43(A315T) have elevated levels of TDP‐43 and protein markers of ER stress (GRP‐78) and autophagy (LC3) in the skin (Wang et al., ). However, it should be noted that a very recent study failed to demonstrate any cytological lesions, including mislocalization of TDP‐43, in the skin of SALS patients (Codron et al., ).…”

Endoplasmic Reticulum Stress Signalling Induces Casein Kinase 1-Dependent Formation of Cytosolic TDP-43 Inclusions in Motor Neuron-Like Cells

“…Tunicamycin induced the most robust formation of TDP-43-positive inclusions and was thus selected for further characterisation. Under conditions of ER stress, chaperones such as Grp78 are known to become activated, a response which is proposed to support correct folding of accumulating proteins [58]. The abundance of the ER chaperone Grp78 (aka BiP) was determined by immunoblotting ( Fig.…”