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.
1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Xuejing
X
Wang
2. Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA.
Shuang
S
Zhou
1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Xuebing
X
Ding
3. Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.
Mingming
M
Ma
3. Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.
Jiewen
J
Zhang
4. Department of Statistics, North Dakota State University, Fargo, ND, 58105, USA.
Yue
Y
Zhou
2. Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA.
Erxi
E
Wu
1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Junfang
J
Teng
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020125:Mutation, Missense; D012867:Skin / Q000378:metabolism / Q000473:pathology*
D015415:Biomarkers; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C000598624:TARDBP protein, human
Amyotrophic lateral sclerosis; Autophagy; Endoplasmic reticulum stress; TDP-43A315T