Journal article
HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
Journal of neurochemistry, v 145(4)
01 May 2018
PMID: 29315562
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Parkinson's disease is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra and iron accumulation in the substantia nigra. The driver underlying iron accumulation remains 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 Parkinson's disease. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants.
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Details
- Title
- HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity
- Creators
- Anne M. Nixon - Penn State Milton S. Hershey Medical CenterMark D. Meadowcroft - Penn State Milton S. Hershey Medical CenterElizabeth B. Neely - Penn State Milton S. Hershey Medical CenterAmanda M. Snyder - Pennsylvania State UniversityCarson J. Purnell - Penn State Milton S. Hershey Medical CenterJustin Wright - Wright Labs, Huntingdon, PA USARegina Lamendella - Juniata CollegeWint Nandar - University of PittsburghXuemei Huang - Penn State Milton S. Hershey Medical CenterJames R. Connor - Penn State Milton S. Hershey Medical Center
- Publication Details
- Journal of neurochemistry, v 145(4)
- Publisher
- Wiley
- Number of pages
- 13
- Grant note
- Penn State Neuroscience Institute Pennsylvania Department of Health Tobacco CURE Funds
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Health Sciences
- Web of Science ID
- WOS:000434133900003
- Scopus ID
- 2-s2.0-85044638384
- Other Identifier
- 991021866417104721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Biochemistry & Molecular Biology
- Neurosciences