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A New Study Finds Iron Dysregulation Has A Role In Neurodegenerative Disease Developement

Iron dysregulation has a role in neurodegenerative disease developement, according to a new study. Various neurodegenerative illnesses, such as Parkinson's disease (PD) and multiple sclerosis (MS), have been linked in the past to iron dysregulation, or variations from "normal" iron metabolism (MS).

Daisy-Mae Schmitt
Jan 19, 202314 Shares14365 Views
Iron dysregulation has a role in neurodegenerative disease developement, according to a new study. Various neurodegenerative illnesses, such as Parkinson's disease (PD) and multiple sclerosis (MS), have been linked in the past to iron dysregulation, or variations from "normal" iron metabolism (MS). To be more specific, microglia (i.e., resident immune cells) loaded with Iron were shown to occupy brain areas linked to these disorders.
Despite the well-established link between iron dysregulation and neurodegenerative diseases, our current understanding of how iron buildup impacts microglial function and neurodegeneration is limited. In order to better understand how microglia react to iron, researchers at the multinational pharmaceutical firm Sanofi recently conducted a study.
For years it has been known that iron accumulates in affected brain regions in PD, MS and other neurodegenerative diseases. This is something we can see in patients using MRI imaging, where it has been shown that iron levels increase over the course of the disease. We also had our own data from progressive MS patients showing iron dysregulation in brain microglia, the resident immune cells of the brain.- Timothy Hammond, Study author

What Are Neurodegenerative Diseases?

Some illnesses of the central and peripheral nervous systems cause nerve cells to gradually lose their ability to function and eventually die, a process known as neurodegeneration. Some therapies may help alleviate the physical or mental symptoms of neurodegenerative disorders, but there are presently no solutions for these conditions and no way to limit their course.
Innumerable individuals all over the globe are afflicted with neurodegenerative disorders. The most prevalent neurodegenerative disorders are Alzheimer's and Parkinson's. According to data from the Alzheimer's Disease Association, 6.2 million Americans may have Alzheimer's disease by the year 2022. The Parkinson's Foundation estimates that one in every hundred people in the United States has Parkinson's.
Age greatly increases one's risk of having a neurodegenerative disorder. As the average lifespan of Americans rises, more people may be afflicted with neurodegenerative disorders in the future decades. Our knowledge of the origins of neurodegenerative illnesses must be expanded, and novel strategies for treating and preventing them must be created.
Researchers have shown that both genetics and environmental factors have a role in an individual's susceptibility to neurodegenerative disorders. Even if a person has a genotype that makes them more likely to develop Parkinson's disease, environmental factors may still have a role in the illness's onset, progression, and severity.

Characteristics of Neurodegenerative Diseases and Advancements in Research

Study Objectives

The current research led by Hammond and his team aimed to learn more about the effects of iron buildup in microglia on the health and function of these cells. Their research expands on earlier investigations including the 2012 discovery of ferroptosis, a kind of cell death that requires iron.
Cell death known as ferroptosis is caused by oxidative damage to lipid membranes caused by iron-dependent lipid peroxidation. The authors of the study postulated that iron overload in microglia makes them more vulnerable to ferroptosis, which in turn might contribute to neurodegenerative disorders.
We had to leverage several approaches in this study, including single cell transcriptomics and CRISPR, but the tool that really allowed us to tease apart these mechanisms was a complex tri-culture of human iPSC-derived cells containing microglia, astrocytes, and neurons—three of the major cell types in the brain. This tool was previously developed by a scientist on my team, Sean Ryan, who is also the lead author of our paper.- Timothy Hammond, Study author
The researchers used a tri-culture technique to cultivate microglia for their tests. The researchers next used a combination of genetic and experimental methods to demonstrate that these microglia are both iron-sensitive and responsive.
In addition, they demonstrated that an iron excess alters the transcriptional status of microglia, a finding that is consistent with the transcriptome profile seen in microglia in brain tissue from dead PD patients. Hammond and coworkers found that iron-induced neurotoxicity in their tri-culture system slowed down dramatically when microglia were eliminated. It's clear that iron excess triggers a response from microglia, which likely plays a major role in neurodegeneration.
We believe microglia are actually trying protect neurons by taking up toxic iron and storing it safely, but over time the microglia become overwhelmed and die, releasing the stored iron and causing the neurons to die too. We have to be careful how we target microglia therapeutically, because they perform lots of beneficial activities, but if we can find a targeted approach this could be an important node for diseases like Parkinson's with excessive iron accumulation.- Timothy Hammond, Study author

Final Words

This is the first research to investigate the potential role of iron-loaded microglia in Parkinson's disease and other neurodegenerative conditions. It has the potential to open the door to future significant findings that might help guide the development of novel treatment strategies for these disorders.
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