How Does Iron Dysregulation Contribute to Neurodegenerative Diseases?

neurodegenerative diseases
Source: Medical Xpress

Past neuroscience research found a link between iron dysregulation and different neurodegenerative diseases. Moreover, brain regions associated with these diseases are full of iron packed microglia. For example, resident immune cells.

There is enough documented information on the association between iron dysregulation and neurodegenerative diseases. But the mechanism behind iron accumulation affecting the physiology of microglia and neurodegeneration is still unknown.

Hence, a study has recently been carried out by the healthcare company Sanofi. The study aims to fill this literature gap by understanding how microglia respond to iron.

Timothy Hammond, one of the researchers of the study said,

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.

Key Objective

The main aim of the recent work by Hammond and his colleagues was to understand how health and functioning are affected by iron accumulation in microglia.

Moreover, the work has been built on previous studies and the 2012 iron-dependent form of cell death discovered, called ferroptosis. The researchers also hypothesized that iron-laden microglia are prone to ferroptosis, which may play a role in neurodegenerative diseases.

Hammod explained,

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.

The experiment was conducted by the researchers by growing microglia in a tri-culture system. With the use of a series of genetic and experimental techniques, the researchers showed that microglia response to iron and are also prone to ferroptosis.

Additionally, the team also showed that iron overlead causes a microglial transcriptional state shift, overlapping with the transcriptomic signature, which is seen in brain tissue microglia from deceased patients with PD. Moreover, when the microglia was removed from the tri-culture system, iron neurotoxicity became slow. Suggesting that microglia responds to iron overload and plays a crucial role in neurodegeneration.

In conclusion, this first every study on iron induced neurotoxicity can make way for various new discoveries and development of therapeutic interventions.

Hammod said,

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.


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