HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity

Publication Date:
2018-01-09
Publisher:
Wiley-Blackwell
Print ISSN:
0022-3042
Electronic ISSN:
1471-4159
Topics:
Medicine
Published by:
http://www.wiley.com/wiley-blackwell
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autor Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
beschreibung Parkinson's disease (PD) is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra (SN) and iron accumulation in the substantia nigra. The driver underlying iron accumulation is unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R 2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R 2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for PD. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants. This article is protected by copyright. All rights reserved.
citation_standardnr 6134125
datenlieferant ipn_articles
feed_copyright The International Society for Neurochemistry
feed_copyright_url http://www.neurochemistry.org/
feed_id 9681
feed_publisher Wiley-Blackwell
feed_publisher_url http://www.wiley.com/wiley-blackwell
insertion_date 2018-01-09
journaleissn 1471-4159
journalissn 0022-3042
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher Wiley-Blackwell
quelle Journal of Neurochemistry
relation http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Fjnc.14299
search_space articles
shingle_author_1 Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
shingle_author_2 Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
shingle_author_3 Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
shingle_author_4 Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
shingle_catch_all_1 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
Parkinson's disease (PD) is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra (SN) and iron accumulation in the substantia nigra. The driver underlying iron accumulation is unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R 2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R 2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for PD. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants. This article is protected by copyright. All rights reserved.
Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
Wiley-Blackwell
0022-3042
00223042
1471-4159
14714159
shingle_catch_all_2 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
Parkinson's disease (PD) is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra (SN) and iron accumulation in the substantia nigra. The driver underlying iron accumulation is unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R 2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R 2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for PD. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants. This article is protected by copyright. All rights reserved.
Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
Wiley-Blackwell
0022-3042
00223042
1471-4159
14714159
shingle_catch_all_3 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
Parkinson's disease (PD) is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra (SN) and iron accumulation in the substantia nigra. The driver underlying iron accumulation is unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R 2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R 2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for PD. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants. This article is protected by copyright. All rights reserved.
Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
Wiley-Blackwell
0022-3042
00223042
1471-4159
14714159
shingle_catch_all_4 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
Parkinson's disease (PD) is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra (SN) and iron accumulation in the substantia nigra. The driver underlying iron accumulation is unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R 2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R 2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for PD. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants. This article is protected by copyright. All rights reserved.
Anne M. Nixon, Mark D. Meadowcroft, Elizabeth B. Neely, Amanda M. Snyder, Carson J. Purnell, Justin Wright, Regina Lamendella, Wint Nandar, Xuemei Huang, James R. Connor
Wiley-Blackwell
0022-3042
00223042
1471-4159
14714159
shingle_title_1 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
shingle_title_2 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
shingle_title_3 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
shingle_title_4 HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
timestamp 2025-06-30T23:31:53.781Z
titel HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
titel_suche HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
topic WW-YZ
uid ipn_articles_6134125