The Hidden Dangers of Iron: Imbalance Affects Brain Health and Trigger Neurodegenerative Diseases
Iron is a vital nutrient crucial in the development of the human brain and its functions. In both cases of iron deficiency and accumulation, molecular changes occur, which are responsible for neurodegenerative diseases and even neuronal death. Understanding the genetic framework behind the irregular levels of iron in the brain aids in improving diagnostic and therapeutic strategies.
Iron distribution varies across different regions of
the healthy adult brain. The basal ganglia are identified with a maximum
concentration of iron, the cerebellum, cortical white matter, grey matter, and
midbrain have low concentrations and the least concentration is identified in
the regions of the medulla, locus coeruleus and pons. The desired levels of
iron across the brain are achieved through iron homeostasis (Figure 1). But
this balance is disrupted due to ageing and the responsible genes. Alongside ageing,
iron level shoots up, affecting the iron distribution, and impacting iron
homeostasis.
Figure 1. Key Metabolic Cellular Pathways Involved in Iron Homeostasis,
Utilization, and Transport
Identification of genes responsible for iron
transportation and homeostasis in the brain involved 29,828 individuals from UK
Biobank. Using whole-exome sequencing (WES) protein-coding variants were
precisely identified across 26 regions of the brain. WES was conducted on 26,789
individuals and 3039 were involved in the replication study. This study
identified 36 genes (Figure 2). Among these genes, 6 had been reported
previously and 29 were newly identified. Not all these genes were directly linked
to iron transportation and homeostasis; some were involved in pathways leading
to iron accumulation which leads to disorders like Parkinson’s disease,
Alzheimer’s disease, and depression.
Figure 2. Exome-wide association analysis of rare and common protein-coding genes
with brain iron across 26 regions (a) Rare variants (b) Common variants
Irregular brain iron levels are a common characteristic
among most neurodegenerative diseases. But the role of iron in causing neural
degeneration, whether the alteration in iron concentration or the iron itself
remains unanswered, as the pathogenic mechanisms related to iron are disease-specific.
Additionally, understanding the interaction of iron with synapses, dopamine and
mitochondria is challenging. Continued research into the molecular mechanism
and the genetic aspects of iron homeostasis is crucial for untangling the
relationship between iron and neurodegeneration.
References:
1. Levi
S, Ripamonti M, Moro AS, Cozzi A. Iron imbalance in neurodegeneration.
Molecular Psychiatry. 2024 Apr;29(4):1139-52. https://doi.org/10.1038/s41380-023-02399-z
2. Gong
W, Fu Y, Wu BS, Du J, Yang L, Zhang YR, Chen SD, Kang J, Mao Y, Dong Q, Tan L.
Whole-exome sequencing identifies protein-coding variants associated with brain
iron in 29,828 individuals. Nature Communications. 2024 Jul 2;15(1):5540. https://doi.org/10.1038/s41467-024-49702-2
Image Credits:
1. Cover Image - https://ausmed-images.s3.ap-southeast-2.amazonaws.com/ausmed.com/ausmed-articles/20170316_cover_V2.jpg
2. Figure 1 - https://www.nature.com/articles/s41380-023-02399-z/figures/2
Comments
Post a Comment