Dioxins and related environmental contaminants increase TDP-43 levels

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 th...

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Bibliographic Details
Published in:	Molecular neurodegeneration Vol. 12; no. 1; pp. 35 - 14
Main Authors:	Ash, Peter E A, Stanford, Elizabeth A, Al Abdulatif, Ali, Ramirez-Cardenas, Alejandra, Ballance, Heather I, Boudeau, Samantha, Jeh, Amanda, Murithi, James M, Tripodis, Yorghos, Murphy, George J, Sherr, David H, Wolozin, Benjamin
Format:	Journal Article
Language:	English
Published:	England BioMed Central 05-05-2017 BMC
Subjects:	Actin Age Alanine ALS Alzheimer's disease Amino acids Amyotrophic Lateral Sclerosis Animal models Animals Basal ganglia Brain - drug effects Carcinogens Cell culture Cell Line Central nervous system Central nervous system diseases Dementia disorders Deoxyribonucleic acid Dioxins Disease DNA DNA-Binding Proteins - biosynthesis DNA-Binding Proteins - drug effects Environmental factors Environmental Pollutants - adverse effects Gene regulation Humans Hypoxia Ligands Male Mice Mice, Inbred C57BL Movement disorders Nervous system Neurodegeneration Neurodegenerative diseases Neurons - drug effects Pathology Pesticides Pluripotency Polychlorinated Dibenzodioxins - adverse effects Polycyclic aromatic hydrocarbons Polycyclic Aromatic Hydrocarbons - adverse effects Promoter Protein aggregation Proteins Receptors, Aryl Hydrocarbon - agonists Stem cells Tobacco Toxicity Transcription Tumor suppressor genes β-Amyloid Promoter Protein aggregation Toxicants Transcription Ataxin-2 Fus Neurodegeneration Gene regulation ALS Alpha-synuclein
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Summary:	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. 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. 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. 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.
ISSN:	1750-1326 1750-1326
DOI:	10.1186/s13024-017-0177-9