The Role of Iron in Neurodegenerative Disorders


Watching a loved one slowly forget everything and everyone in their lives is a painful ordeal, which can be even more aggravating if there is no underlying cause. If a cause cannot be pinpointed, it becomes difficult to justify why such an instance of forgetfulness is occurring. Diseases do not discriminate; major influencers such as Stephen Hawking, Lou Gehrig, Michael J. Fox, Muhammad Ali, and Janet Reno have all suffered from neurodegenerative disorders. But, what is it that causes these disorders? Does it have to do with a person’s lifestyle or genetic predisposition? In actuality, scientists have recently found that the accumulation of iron and iron misregulation in the brain cause neuronal death, which in turn leads to neurodegenerative disorders (Qian, et al, 1998).

Our body needs iron to produce hemoglobin (Cole, 2014). Hemoglobin is the protein that helps red blood cells carry oxygen throughout the body. However, a lack of iron results in reduced levels of hemoglobin, which thereby reduces the amount of oxygen your body is actually absorbing. Being that iron is the most abundant trace metal in the brain, a problem may occur when the iron starts to accumulate and is misregulated.

Researchers have found that mutations in the genes that are supposed to regulate the iron content in the brain are what lead to the misregulation. These mutations can have genetic and non-genetic causes (Ke, et al, 2003). For example, neuroferritinopathy is a movement disorder caused by accumulation of iron in the basal ganglia. The basal ganglia is a group of neurons located deep within the cerebral hemispheres and are primarily involved in processing movement related information. They also process information related to emotions, motivations, and cognitive function. On the other hand, Friedreich’s ataxia is a genetic disease that causes progressive damage to the nervous system. Both of these diseases are associated with mutations in genes that encode proteins and are involved in iron metabolism (Zecca, et al, 2004).

Iron accumulation in the brain is thought to be normal as a person ages. However, high concentrations in certain areas such as the basal ganglia, have been linked to Alzheimer’s and Parkinson’s diseases, both of which are neurodegenerative disorders. In Alzheimer’s disease, iron accumulates in the brain without the age-relate increase in ferritin, which increases the risk of oxidative stress (Zecca, et al, 2004). Oxidative stress is harmful because it disrupts the normal functioning of the cell. Oxidative stress may damage the brain tissue therapy, worsening the progression of the disease or making an individual more susceptible to acquiring a new disease. It is also thought to increase plaque formation through its effects on protein processing. Parkinson’s disease is also associated with the accumulation of iron in the substantia nigra (Zecca, et al, 2004). The substantia nigra is a part of the basal ganglia, and produces the majority of the dopamine that originates in the brain. It is thought to play important roles in learning, drug addiction, emotion, and movement. This causes an increase in oxidative stress and protein aggregation, specifically of the alpha synuclei–the main component in Lewy bodies (Zecca, et al, 2004). Lewy bodies are abnormal aggregates of protein that develop in nerve cells, and are pathological  indicators of Parkinson’s disease.

Researchers believe that if we can understand the timing of iron mismanagement in relation to the loss of neurons in neurodegenerative disorders during aging that such observations can be used as a marker of disease progression. Also, it may assist in diagnosing these disorders before symptoms start to show. This information is also being used to develop new therapeutic strategies for the treatment of neurodegenerative disorders involving iron misregulation. Metal chelators have been used to try and reduce iron concentration in the brain, however there is no significant evidence of its clinical impact (Dusek, 2016). Iron removal therapy has been shown to slow down the progression of neurodegenerative disorders, and may even be able to prevent neurodegeneration. By preventing neurodegeneration, the goal of eradicating neurodegenerative disorders will be closer in reach.

References:

Cole, C., M.D. (2014, June 23). Why is Iron Important in My Diet?[PDF]. University of Michigan Health System.

Dusek, P., Schneider, S. A., & Aaseth, J. (2016, December). Iron chelation in the treatment of neurodegenerative diseases. Retrieved September 16, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/27033472

Ke, Y., & Qian, Z. M. (2003). Iron misregulation in the brain: A primary cause of neurodegenerative disorders. The Lancet Neurology, 2(4), 246-253. doi:10.1016/s1474-4422(03)00353-3

Qian, Z. M., & Wang, Q. (1998). Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders. Brain Research Reviews, 27(3), 257-267. doi:10.1016/s0165-0173(98)00012-5

Zecca, L., Youdim, M. B., Riederer, P., Connor, J. R., & Crichton, R. R. (2004). Iron, brain ageing and neurodegenerative disorders [Abstract]. Nature Reviews. Retrieved September 16, 2018, from https://www.nature.com/articles/nrn1537#references.

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