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

Autor: Elizabeth B. Neely, James R. Connor, Mark D. Meadowcroft, Carson J. Purnell, Amanda M. Snyder, Wint Nandar, Xuemei Huang, Anne M. Nixon, Justin P. Wright, Regina Lamendella
Rok vydání: 2017
Předmět:
0301 basic medicine
Paraquat
congenital
hereditary
and neonatal diseases and abnormalities
medicine.medical_specialty
Parkinson's disease
Genotype
Tyrosine 3-Monooxygenase
Substantia nigra
Mice
Transgenic
Biology
Biochemistry
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Mice
0302 clinical medicine
Internal medicine
medicine
Animals
education
Hemochromatosis Protein
education.field_of_study
Microglia
Tyrosine hydroxylase
Herbicides
Neurotoxicity
nutritional and metabolic diseases
Brain
Genetic Variation
Parkinson Disease
medicine.disease
Gastrointestinal Microbiome
Disease Models
Animal
030104 developmental biology
Endocrinology
medicine.anatomical_structure
chemistry
Gene-Environment Interaction
Neurotoxicity Syndromes
HFE Protein
030217 neurology & neurosurgery
Immunostaining
Zdroj: Journal of neurochemistry. 145(4)
ISSN: 1471-4159
Popis: 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 R2 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 R2 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.
Databáze: OpenAIRE
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