By Richard Row, Ph.D.
Understanding Brain Health
Building and maintaining a healthy brain requires thousands of distinct processes to be exquisitely balanced throughout decades of life. Extensive research in recent decades has found this equilibrium is disrupted in brains that are aging or undergoing degeneration. However it isn’t clear whether these disturbances are a cause or a consequence of degeneration. New research is shedding light on this question and demonstrating a key role for oxidative stress in triggering breakdowns in brain health.
A Window to Understanding Causes of Mental Decline
Clues to understanding brain health have come from extensive work linking specific gene mutations to an increased risk of early cognitive decline. Although such mutations are not the most common cause of neurodegeneration they provide a window into mechanisms that may be generally relevant. One attractive unifying hypothesis is that degeneration is caused by accumulated damage to DNA, proteins and other macromolecules resulting from oxidative stress. Many mutations linked with neurodegeneration have been shown to cause increased oxidative stress in the brain, such as a mutation in the HFE gene which acts to regulate iron levels in neurons. Misregulation of iron can lead to overproduction of free radicals which results in oxidative stress. A mouse model of the human HFE mutation has been used in multiple studies to shed light on the link between the mutation, iron regulation, and neurodegeneration.
Regulating Iron Levels and Oxidative Stress in the Brain
Mutations in the HFE gene were identified and linked with a conditional called hereditary hemochromatosis over twenty years ago. Among several identified mutations is a single nucleotide change that results in an amino acid change in the protein. The equivalent mutation in mouse is H67D and professor James Connor at The Pennsylvania State University worked with ingenious to create a new mouse model expressing this mutant form of the HFE gene. This model has been used in multiple studies aimed at understanding processes at work in the aging brain including projects related to cholesterol metabolism, iron levels and oxidative stress, and Parkinson’s disease.
In a recently published article The Connor Lab demonstrated that mice expressing the mutant H67D-HFE have higher levels of the iron-storing protein ferritin in their brains, although total iron levels were observed to be equal to wild-type levels. The high level of ferritin may explain another observation, that H67D-HFE expression protects mice from the effects of paraquat injection which usually leads to Parkinson’s-like damage to the brain. The study’s authors suggest that since paraquat is known to increase levels of iron in the brain the higher level of ferritin may counter this effect by binding the extra iron. It’s possible that producing extra ferritin may reduce oxidative stress by preventing iron from creating free radicals. Further studies will illuminate the balance of iron, ferritin, and oxidative stress that must be properly regulated to preserve a healthy brain.
- Nixon AM, Meadowcroft MD, Neely EB, Snyder AM, Purnell CJ, Wright J, Lamendella R, Nandar W, Huang X. and Connor JR. 2018. HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity. J Neurochem 145(4):299-311.