Aging Brain Accumulates Iron (Fe), Found Neural Cell Response Method

A research illustration summarizing the amount of iron accumulated in the substantia nigra according to age and its corresponding effects.

[Asia Economy Yeongnam Reporting Headquarters, Reporter Hwang Dooyul] A research team at Ulsan National Institute of Science and Technology (UNIST) has discovered genes that respond to iron accumulation in the brain.

As humans age, iron (Fe) accumulates in the brain. Excess iron can kill brain cells and cause neurodegenerative diseases, but this is not always the case. Our bodies have a plan to respond to iron accumulation in the brain.

The research team led by Professors Kwon Taejun and Cho Hyungjun from the Department of Biomedical Engineering at UNIST revealed the "neuronal response mechanism to iron accumulation in the brain with aging" through joint research.

Through experiments using aging animal models and cell lines, the team found that the genes related to protein misfolding, CLU (Clusterin) and HERPUD1 (Homocysteine-Inducible ER Protein with Ubiquitin-Like Domain 1), play important roles in alleviating iron toxicity.

Heavy metals like iron are essential for our body but generate reactive oxygen species that are toxic and can cause DNA damage or cell death.

It is known that iron accumulates in specific parts of the brain as we age. Parkinson’s disease, a representative neurodegenerative disorder, is thought to be influenced by cell death caused by iron accumulation in the brain’s substantia nigra (SN) during aging.

However, not everyone develops neurodegenerative diseases despite iron deposition in the substantia nigra with age. There is a mechanism that protects brain cells from toxicity caused by accumulated iron.

To identify this mechanism, Professors Kwon Taejun and Cho Hyungjun compared magnetic resonance imaging (MRI) scans of "old and young mice" and identified related genes, followed by validation experiments using cell lines.

MRI scans of the substantia nigra in old and young mice quantitatively confirmed that iron accumulates in this brain region with age.

The researchers directly collected tissue from this area to analyze gene expression and studied the functions of genes whose expression increased with aging in the substantia nigra.

Gene analysis using mouse brain tissue revealed not only genes responding to increased iron concentration but also various genes related to development and aging.

Cell line validation experiments confirmed that the two genes related to protein misfolding, CLU and HERPUD1, respond to elevated iron levels.

When the expression of CLU and HERPUD1 genes was reduced in cell lines, cell death due to iron deposition increased. This indicates that these two genes play an important role in protecting brain cells from iron accumulation associated with aging.

Professor Cho Hyungjun explained about this study, “By combining magnetic resonance imaging (MRI) technology that can measure iron and functional genomics technology that analyzes cellular responses to iron at the molecular level, we were able to identify new genes related to iron accumulation during aging.”

Professor Kwon Taejun said, “Compared to previous research on neurodegenerative diseases, studies on iron naturally accumulating in brain tissue with age have been insufficient. The genes discovered this time will help research the relationship between aging-related neurodegenerative diseases and iron.”

The research was supported by the National Research Foundation of Korea’s University Leading Research Center Support Project, Global PhD Fellowship, Korea Health Industry Development Institute’s Health and Medical Research and Development Project, and UNIST’s Future Leading Specialized Project.

The research results are scheduled to be published in "Aging Cell," published by Wiley, and are currently available online ahead of print.

(From left) Professor Kwon Tae-jun, Researcher Jo Hwa-pyeong, Researcher Kwon Gu-jin, and Professor Jo Hyung-jun are gathered in front of the MRI equipment used in the study.

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