HFE Mutations in Neurodegenerative Disease as a Model of Hormesis

Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze re...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-03, Vol.25 (6), p.3334
Main Authors: Marshall Moscon, Savannah L, Connor, James R
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Analysis
Animals
Brain research
Disease
Genetic aspects
Hemochromatosis Protein - genetics
HFE
Histocompatibility Antigens Class I - genetics
Homeostasis
Hormesis
iron
Iron - metabolism
Metabolism
Mice
Mutation
Nervous system diseases
Neurodegeneration
Neurodegenerative Diseases - genetics
neuroprotection
Oxidative stress
Pathology
Proteins
Review
Toxins
White people
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Summary:Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze reactive oxygen species production. However, whether HFE variants exacerbate or protect against neurodegeneration has been heavily debated. Some claim that mutated HFE exacerbates oxidative stress and neuroinflammation, thus predisposing carriers to neurodegeneration-linked pathologies. However, H63D HFE has also been shown to slow the progression of multiple neurodegenerative diseases and to protect against environmental toxins that cause neurodegeneration. These conflicting results showcase the need to further understand the contribution of HFE variants to neurodegenerative disease heterogeneity. Data from mouse models consistently demonstrate robust neuroprotection against toxins known to increase the risk of neurodegenerative disease. This may represent an adaptive, or hormetic, response to increased iron, which leaves cells better protected against future stressors. This review describes the current research regarding the contribution of HFE variants to neurodegenerative disease prognosis in the context of a hormetic model. To our knowledge, this is the first time that a hormetic model for neurodegenerative disease has been presented.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25063334