Dioxins and related environmental contaminants increase TDP-43 levels

Abstract

BackgroundAmyotrophic 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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 materialThe online version of this article (doi:10.1186/s13024-017-0177-9) contains supplementary material, which is available to authorized users.

The Aryl Hydrocarbon Receptor and the Nervous System

“…Indeed, high levels of NO are suspected to activate the mitochondrial apoptotic pathway. Finally, the AhR has been identified as a regulator of TDP-43 expression, a biomarker of the development of amyotrophic lateral sclerosis (ALS), suggesting for the first time that a potential link exists between environmental ligands and the development of these neurodegenerative diseases [ 130 ].…”

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

“…FICZ (100 nM) enhanced the level of TDP-43 protein in iPSCs derived from a patient with ALS that had differentiated into neurons. Moreover, in human neuroblastoma M17 cells 500 nM FICZ raised TDP-43 levels and stabilized this protein; while in H4 neuroglioma cells this same concentration increased the expression of the TARDBP, SOD1, PON2, and C9ORF72 genes associated with ALS (Ash et al 2017). Accordingly, environmental chemicals that lead to sustained activation of AHR signaling or block metabolic degradation of FICZ might be significant risk factors for ALS.…”

“…Multiple investigations have observed a potential association between environmental AHR ligands and an increased risk for developing ALS. In this context Ash et al (2017) reported that AHR ligands elevated the amount of aggregated TAR DNA-Binding Protein-43 (TDP-43) in human cell lines, in iPSCs, and even in the murine brain. FICZ (100 nM) enhanced the level of TDP-43 protein in iPSCs derived from a patient with ALS that had differentiated into neurons.…”

Amyotrophic lateral sclerosis—A case report and mechanistic review of the association with toluene and other volatile organic compounds

“…Transactivation response (TAR) DNA‐ binding protein 43 (TDP‐43) and ubiquitin inclusions are the only biomarkers for sporadic ALS . Aromatic hydrocarbon receptor agonists such as dioxin have been shown to increase brain levels of TDP‐43 in human neuronal cell lines, motor neuron differentiated induced pluripotent stem cells, and in murine brain indicating that these compounds are risk factors for ALS …”