Dioxins and related environmental contaminants increase TDP-43 levels

Abstract 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Peter E. A. Ash [verfasserIn] Elizabeth A. Stanford [verfasserIn] Ali Al Abdulatif [verfasserIn] Alejandra Ramirez-Cardenas [verfasserIn] Heather I. Ballance [verfasserIn] Samantha Boudeau [verfasserIn] Amanda Jeh [verfasserIn] James M. Murithi [verfasserIn] Yorghos Tripodis [verfasserIn] George J. Murphy [verfasserIn] David H. Sherr [verfasserIn] Benjamin Wolozin [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	Neurodegeneration ALS Protein aggregation Promoter Transcription Gene regulation

Übergeordnetes Werk:	In: Molecular Neurodegeneration - BMC, 2007, 12(2017), 1, Seite 14
Übergeordnetes Werk:	volume:12 ; year:2017 ; number:1 ; pages:14

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13024-017-0177-9

Katalog-ID:	DOAJ057549818

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520			\|a Abstract 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.
650		4	\|a Neurodegeneration
650		4	\|a ALS
650		4	\|a Protein aggregation
650		4	\|a Promoter
650		4	\|a Transcription
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653		0	\|a Neurology. Diseases of the nervous system
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700	0		\|a David H. Sherr \|e verfasserin \|4 aut
700	0		\|a Benjamin Wolozin \|e verfasserin \|4 aut
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allfields	10.1186/s13024-017-0177-9 doi (DE-627)DOAJ057549818 (DE-599)DOAJ918a0164aa8e4ba8b9e5f89dd64cfaf5 DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Peter E. A. Ash verfasserin aut Dioxins and related environmental contaminants increase TDP-43 levels 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Neurodegeneration ALS Protein aggregation Promoter Transcription Gene regulation Neurology. Diseases of the nervous system Geriatrics Elizabeth A. Stanford verfasserin aut Ali Al Abdulatif verfasserin aut Alejandra Ramirez-Cardenas verfasserin aut Heather I. Ballance verfasserin aut Samantha Boudeau verfasserin aut Amanda Jeh verfasserin aut James M. Murithi verfasserin aut Yorghos Tripodis verfasserin aut George J. Murphy verfasserin aut David H. Sherr verfasserin aut Benjamin Wolozin verfasserin aut In Molecular Neurodegeneration BMC, 2007 12(2017), 1, Seite 14 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:12 year:2017 number:1 pages:14 https://doi.org/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/article/918a0164aa8e4ba8b9e5f89dd64cfaf5 kostenfrei http://link.springer.com/article/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2017 1 14
spelling	10.1186/s13024-017-0177-9 doi (DE-627)DOAJ057549818 (DE-599)DOAJ918a0164aa8e4ba8b9e5f89dd64cfaf5 DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Peter E. A. Ash verfasserin aut Dioxins and related environmental contaminants increase TDP-43 levels 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Neurodegeneration ALS Protein aggregation Promoter Transcription Gene regulation Neurology. Diseases of the nervous system Geriatrics Elizabeth A. Stanford verfasserin aut Ali Al Abdulatif verfasserin aut Alejandra Ramirez-Cardenas verfasserin aut Heather I. Ballance verfasserin aut Samantha Boudeau verfasserin aut Amanda Jeh verfasserin aut James M. Murithi verfasserin aut Yorghos Tripodis verfasserin aut George J. Murphy verfasserin aut David H. Sherr verfasserin aut Benjamin Wolozin verfasserin aut In Molecular Neurodegeneration BMC, 2007 12(2017), 1, Seite 14 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:12 year:2017 number:1 pages:14 https://doi.org/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/article/918a0164aa8e4ba8b9e5f89dd64cfaf5 kostenfrei http://link.springer.com/article/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2017 1 14
allfields_unstemmed	10.1186/s13024-017-0177-9 doi (DE-627)DOAJ057549818 (DE-599)DOAJ918a0164aa8e4ba8b9e5f89dd64cfaf5 DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Peter E. A. Ash verfasserin aut Dioxins and related environmental contaminants increase TDP-43 levels 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Neurodegeneration ALS Protein aggregation Promoter Transcription Gene regulation Neurology. Diseases of the nervous system Geriatrics Elizabeth A. Stanford verfasserin aut Ali Al Abdulatif verfasserin aut Alejandra Ramirez-Cardenas verfasserin aut Heather I. Ballance verfasserin aut Samantha Boudeau verfasserin aut Amanda Jeh verfasserin aut James M. Murithi verfasserin aut Yorghos Tripodis verfasserin aut George J. Murphy verfasserin aut David H. Sherr verfasserin aut Benjamin Wolozin verfasserin aut In Molecular Neurodegeneration BMC, 2007 12(2017), 1, Seite 14 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:12 year:2017 number:1 pages:14 https://doi.org/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/article/918a0164aa8e4ba8b9e5f89dd64cfaf5 kostenfrei http://link.springer.com/article/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2017 1 14
allfieldsGer	10.1186/s13024-017-0177-9 doi (DE-627)DOAJ057549818 (DE-599)DOAJ918a0164aa8e4ba8b9e5f89dd64cfaf5 DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Peter E. A. Ash verfasserin aut Dioxins and related environmental contaminants increase TDP-43 levels 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Neurodegeneration ALS Protein aggregation Promoter Transcription Gene regulation Neurology. Diseases of the nervous system Geriatrics Elizabeth A. Stanford verfasserin aut Ali Al Abdulatif verfasserin aut Alejandra Ramirez-Cardenas verfasserin aut Heather I. Ballance verfasserin aut Samantha Boudeau verfasserin aut Amanda Jeh verfasserin aut James M. Murithi verfasserin aut Yorghos Tripodis verfasserin aut George J. Murphy verfasserin aut David H. Sherr verfasserin aut Benjamin Wolozin verfasserin aut In Molecular Neurodegeneration BMC, 2007 12(2017), 1, Seite 14 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:12 year:2017 number:1 pages:14 https://doi.org/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/article/918a0164aa8e4ba8b9e5f89dd64cfaf5 kostenfrei http://link.springer.com/article/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2017 1 14
allfieldsSound	10.1186/s13024-017-0177-9 doi (DE-627)DOAJ057549818 (DE-599)DOAJ918a0164aa8e4ba8b9e5f89dd64cfaf5 DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Peter E. A. Ash verfasserin aut Dioxins and related environmental contaminants increase TDP-43 levels 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Neurodegeneration ALS Protein aggregation Promoter Transcription Gene regulation Neurology. Diseases of the nervous system Geriatrics Elizabeth A. Stanford verfasserin aut Ali Al Abdulatif verfasserin aut Alejandra Ramirez-Cardenas verfasserin aut Heather I. Ballance verfasserin aut Samantha Boudeau verfasserin aut Amanda Jeh verfasserin aut James M. Murithi verfasserin aut Yorghos Tripodis verfasserin aut George J. Murphy verfasserin aut David H. Sherr verfasserin aut Benjamin Wolozin verfasserin aut In Molecular Neurodegeneration BMC, 2007 12(2017), 1, Seite 14 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:12 year:2017 number:1 pages:14 https://doi.org/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/article/918a0164aa8e4ba8b9e5f89dd64cfaf5 kostenfrei http://link.springer.com/article/10.1186/s13024-017-0177-9 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2017 1 14
language	English
source	In Molecular Neurodegeneration 12(2017), 1, Seite 14 volume:12 year:2017 number:1 pages:14
sourceStr	In Molecular Neurodegeneration 12(2017), 1, Seite 14 volume:12 year:2017 number:1 pages:14
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Neurodegeneration ALS Protein aggregation Promoter Transcription Gene regulation Neurology. Diseases of the nervous system Geriatrics
isfreeaccess_bool	true
container_title	Molecular Neurodegeneration
authorswithroles_txt_mv	Peter E. A. Ash @@aut@@ Elizabeth A. Stanford @@aut@@ Ali Al Abdulatif @@aut@@ Alejandra Ramirez-Cardenas @@aut@@ Heather I. Ballance @@aut@@ Samantha Boudeau @@aut@@ Amanda Jeh @@aut@@ James M. Murithi @@aut@@ Yorghos Tripodis @@aut@@ George J. Murphy @@aut@@ David H. Sherr @@aut@@ Benjamin Wolozin @@aut@@
publishDateDaySort_date	2017-01-01T00:00:00Z
hierarchy_top_id	515978361
id	DOAJ057549818
language_de	englisch
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Ash</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Dioxins and related environmental contaminants increase TDP-43 levels</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract 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. 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callnumber-first	R - Medicine
author	Peter E. A. Ash
spellingShingle	Peter E. A. Ash misc RC346-429 misc RC952-954.6 misc Neurodegeneration misc ALS misc Protein aggregation misc Promoter misc Transcription misc Gene regulation misc Neurology. Diseases of the nervous system misc Geriatrics Dioxins and related environmental contaminants increase TDP-43 levels
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topic_title	RC346-429 RC952-954.6 Dioxins and related environmental contaminants increase TDP-43 levels Neurodegeneration ALS Protein aggregation Promoter Transcription Gene regulation
topic	misc RC346-429 misc RC952-954.6 misc Neurodegeneration misc ALS misc Protein aggregation misc Promoter misc Transcription misc Gene regulation misc Neurology. Diseases of the nervous system misc Geriatrics
topic_unstemmed	misc RC346-429 misc RC952-954.6 misc Neurodegeneration misc ALS misc Protein aggregation misc Promoter misc Transcription misc Gene regulation misc Neurology. Diseases of the nervous system misc Geriatrics
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title	Dioxins and related environmental contaminants increase TDP-43 levels
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title_full	Dioxins and related environmental contaminants increase TDP-43 levels
author_sort	Peter E. A. Ash
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author_browse	Peter E. A. Ash Elizabeth A. Stanford Ali Al Abdulatif Alejandra Ramirez-Cardenas Heather I. Ballance Samantha Boudeau Amanda Jeh James M. Murithi Yorghos Tripodis George J. Murphy David H. Sherr Benjamin Wolozin
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title_sort	dioxins and related environmental contaminants increase tdp-43 levels
callnumber	RC346-429
title_auth	Dioxins and related environmental contaminants increase TDP-43 levels
abstract	Abstract 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.
abstractGer	Abstract 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.
abstract_unstemmed	Abstract 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.
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title_short	Dioxins and related environmental contaminants increase TDP-43 levels
url	https://doi.org/10.1186/s13024-017-0177-9 https://doaj.org/article/918a0164aa8e4ba8b9e5f89dd64cfaf5 http://link.springer.com/article/10.1186/s13024-017-0177-9 https://doaj.org/toc/1750-1326
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