By Richard Row, Ph.D.
Understanding Brain Health
Decades of intense study have shown that the processes involved in neurodegeneration are inextricably linked to those required for the formation and maintenance of a healthy brain. Thousands of distinct molecular mechanisms must be exquisitely balanced to preserve a healthy, functioning organ through decades of life, and this balance is found to be disrupted during neurodegeneration. However it isn’t yet clear whether such disruptions are the primary cause of degeneration or rather a secondary effect. Clues to these mysteries have come from extensive work linking specific gene mutations to an increased risk of early cognitive decline in mouse models. 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 by free radicals. This idea is supported by the identification of mutations linked with neurodegeneration that also cause increased free radical production, such as a mutation in the HFE gene which acts to regulate iron levels in neurons. Mis-regulation of iron in the brain has been observed during neurodegeneration and iron can be a potent source of free radicals if not properly regulated. 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.
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 base change that results in an aspartic acid being present at position 63 of the human protein, in place of a histidine. 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.
The Delicate Balance
In a recently published article the Connor lab demonstrated that mice expressing H67D-HFE express 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. Further studies will illuminate the delicate balance of interacting pathways that must be properly maintained to preserve a healthy brain. Read more on humanized mice models.
Nixon, A.M., Meadowcroft, M.D., Neely, E.B., Snyder, A.M., Purnell, C.J., Wright, J., Lamendella, R., Nandar, W., Huang, X. and Connor, J.R. “HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity”. Journal of neurochemistry (2018).