期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 11, 期 10, 页码 1140-1149出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.12657
关键词
TDP-43(A315T); Endoplasmic reticulum stress; Autophagy; Amyotrophic lateral sclerosis
资金
- National Natural Science Foundation of China [81471307, 81301086, 81100881, 81100949]
- Youth Innovation Fund of The First Affiliated Hospital of Zhengzhou University
- 5451 Project of Health Department of Henan Province [201201007]
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.
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