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.

International Journal of Biological Sciences
Xuejing WangJunfang Teng

Abstract

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...Continue Reading

Citations

Oct 27, 2017·Molecular Neurodegeneration·Csaba KonradGiovanni Manfredi
Dec 18, 2018·Human Mutation·Georgios PampalakisGeorge P Patrinos
Feb 6, 2019·Acta Neuropathologica·Katja Burk, R Jeroen Pasterkamp
May 26, 2018·Neurochemical Research·Kazuki OhuchiMasamitsu Shimazawa
Jun 2, 2020·Frontiers in Cellular Neuroscience·Ximena Paez-ColasanteEva L Feldman
Jun 15, 2017·Frontiers in Molecular Neuroscience·Mauricio BudiniAlfredo Criollo
Apr 20, 2021·Frontiers in Cellular Neuroscience·Ruxandra DafincaKevin Talbot
Apr 30, 2021·Frontiers in Cellular Neuroscience·Caterina PeggionRaffaele Lopreiato
May 6, 2021·International Journal of Molecular Sciences·Alistair WoodSarah Lyn Rea

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Methods Mentioned

BETA
protein folding
PCR
transfection
biopsy

Software Mentioned

SPSS

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