Dioxins and related environmental contaminants increase TDP-43 levels
| Autor: | Yorghos Tripodis, Alejandra Ramirez-Cardenas, David H. Sherr, George J. Murphy, Heather I. Ballance, James M. Murithi, Peter E.A. Ash, Samantha Boudeau, Ali Al Abdulatif, Benjamin Wolozin, Elizabeth A. Stanford, Amanda Jeh |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Polychlorinated Dibenzodioxins lcsh:Geriatrics lcsh:RC346-429 Mice 0302 clinical medicine Toxicants Polycyclic Aromatic Hydrocarbons Induced pluripotent stem cell Ataxin-2 Regulation of gene expression Neurons Gene knockdown biology Chemistry Neurodegeneration Brain 3. Good health DNA-Binding Proteins Biochemistry Environmental Pollutants Protein aggregation Transcription Research Article TARDBP Cell Line Alpha-synuclein 03 medical and health sciences Cellular and Molecular Neuroscience medicine Animals Humans Molecular Biology Transcription factor Carcinogen lcsh:Neurology. Diseases of the nervous system Fus Amyotrophic Lateral Sclerosis Promoter medicine.disease Aryl hydrocarbon receptor Gene regulation Mice Inbred C57BL lcsh:RC952-954.6 030104 developmental biology Receptors Aryl Hydrocarbon biology.protein Cancer research Neurology (clinical) ALS 030217 neurology & neurosurgery |
| Zdroj: | Molecular Neurodegeneration, Vol 12, Iss 1, Pp 1-14 (2017) Molecular Neurodegeneration |
| ISSN: | 1750-1326 |
| DOI: | 10.1186/s13024-017-0177-9 |
| Popis: | Background Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition that is characterized by progressive loss of motor neurons and the accumulation of aggregated TAR DNA Binding Protein-43 (TDP-43, gene: TARDBP). Increasing evidence indicates that environmental factors contribute to the risk of ALS. Dioxins, related planar polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants that activate the aryl hydrocarbon receptor (AHR), a ligand-activated, PAS family transcription factor. Recently, exposure to these toxicants was identified as a risk factor for ALS. Methods We examined levels of TDP-43 reporter activity, transcript and protein. Quantification was done using cell lines, induced pluripotent stem cells (iPSCs) and mouse brain. The target samples were treated with AHR agonists, including 6-Formylindolo[3,2-b]carbazole (FICZ, a potential endogenous ligand, 2,3,7,8-tetrachlorodibenzo(p)dioxin, and benzo(a)pyrene, an abundant carcinogen in cigarette smoke). The action of the agonists was inhibited by concomitant addition of AHR antagonists or by AHR-specific shRNA. Results We now report that AHR agonists induce up to a 3-fold increase in TDP-43 protein in human neuronal cell lines (BE-M17 cells), motor neuron differentiated iPSCs, and in murine brain. Chronic treatment with AHR agonists elicits over 2-fold accumulation of soluble and insoluble TDP-43, primarily because of reduced TDP-43 catabolism. AHR antagonists or AHR knockdown inhibits agonist-induced increases in TDP-43 protein and TARDBP transcription demonstrating that the ligands act through the AHR. Conclusions These results provide the first evidence that environmental AHR ligands increase TDP-43, which is the principle pathological protein associated with ALS. These results suggest novel molecular mechanisms through which a variety of prevalent environmental factors might directly contribute to ALS. The widespread distribution of dioxins, PCBs and PAHs is considered to be a risk factor for cancer and autoimmune diseases, but could also be a significant public health concern for ALS. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0177-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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