Ferroptosis of Microglia Drives Neurodegeneration

Brent R. Stockwell, Ph.D.
3 min readDec 27, 2022

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A recent paper from Tim Hammond reports that microglia in the brain drive neurodegenerative diseases by undergoing ferroptosis.

Neurodegenerative diseases are among the most challenging diseases for patients and drug hunters. These diseases include Parkinson’s Disease, Huntington Disease, Alzheimer’s Disease, and ALS, among others. It has been frustratingly difficult to identify driving mechanisms and to create curative therapies for these diseases for many decades. Thus, elucidating mechanisms driving these diseases is an important step on the path to a greater understanding that will generate therapeutic hypotheses.

Human brain (generated with Jasper.ai)

In a recently published paper in Nature Neuroscience, Tim Hammond and his colleagues at Sanofi reported that microglia have an unappreciated role in neurodegenerative diseases.

Microglia (small glia) are non-neuronal glial cells found in the brain that act as local guardians against damage and infection, but can drive inflammation when activated. It turns out that they are highly susceptible to death by ferroptosis.

Microglial cells (created with Jasper.ai)

Microglia are rich in iron, a key driver of ferroptosis — a form of cell death discovered in my lab in 2012 and in parallel in Marcus Conrad’s lab through his genetic studies of GPX4.

Image of a cell undergoing ferroptosis (created by Nicoletta Barolini)

Dr. Hammond and his colleagues explored the idea that microglia might undergo ferroptosis and that this might be a pathological event in some neurodegenerative diseases.

To test this idea, they created a novel tri-culture system in which induced pluripotent stem cells were used to create neurons, astrocytes, and microglia. Among the three cell types in their culture system, they found that microglia were the most responsive to iron.

Schematic depiction of a triculture system (generated with Jasper.ai)

Strikingly, the authors found that microglia undergoing ferroptosis in response to iron overload had a distinct transcriptional signature, and that this signature is found in the spinal cord of ALS patients and the brain of Parkinson’s Disease patients.

Moreover, in their triculture system, microglia drove the death of neurons, and removing microglia protected neurons from death.

Dr. Hammond and his colleagues then performed a CRISPR genetic screen to identify unique regulators of ferroptosis in microglia, and discovered that SEC24B is essential for microglia ferroptosis. SEC24B is known to be a regulator of vesicle trafficking from the endoplasmic reticulum to the golgi. Moreover, they found that SEC24B is more abundant in neurodegenerative diseases, perhaps enhancing sensitivity to ferroptosis.

Predicted SEC24B structure (from UniProt, predicted by AlphaFold)

The mechanism by which SEC24B contributes to ferroptosis wasn’t entirely clear in the paper — they suggest that perhaps SEC24B controls the labile iron pool, which is important for ferroptosis.

However, my lab reported recently that the iron transporter protein TfR1 (Transferrin Receptor Protein 1) is upregulated and moves to the plasma membrane of cells undergoing ferroptosis. This drives a further increase in iron levels during ferroptosis. I wonder if SEC24B is required for this mobilization of TfR1 during ferroptosis in microglia and if this could explain the key role of SEC24B in these cells.

Overall, this is an exciting breakthrough because it suggests that blocking ferroptosis in microglia could slow or prevent some of these tragic neurodegenerative diseases.

Congratulations to Dr. Hammond and the Sanofi team on an exciting set of discoveries in their paper! Their work opens up an exciting new therapeutic target for neurodegenerative diseases.

Apotential treatment for neurodegeneration driven by iron damage (generated by DALL·E2)

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Brent R. Stockwell, Ph.D.
Brent R. Stockwell, Ph.D.

Written by Brent R. Stockwell, Ph.D.

Chair and Professor of Biological Sciences at Columbia University. Top Medium writer in Science, Creativity, Health, and Ideas

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