Accumulation of iron in the brain is a common feature of several neurodegenerative diseases including Alzheimer's and Parkinson's disease. Although the pathogenic relevance of iron has long been controversial, recent studies have shown that impaired iron homeostasis is associated with the progression of these disorders. Presumably, the immunocompetent microglia in the brain plays a crucial role here, as it has the highest iron storage capacity. Exactly how iron overload affects microglial function and whether iron-loaded microglia contribute to neurodegeneration was previously unknown.
A recent study by Sean Ryan and colleagues has now shown that microglial cells derived from human induced pluripotent stem cells are highly sensitive to iron. They become susceptible to so-called ferroptosis, an iron-dependent form of cell death (see also section 2.1.2.1 in my book on neurodegeneration). In addition, elevated iron leads to altered gene expression similar to that seen in Parkinson's disease patients. In particular, glutathione metabolism and dysregulated immune- and myeloid-related signaling pathways are affected. Interestingly, earlier single-cell analyses in AD patients already identified impaired iron homeostasis in microglia.
Since removal of microglia from the cell culture system significantly delayed iron-induced neurotoxicity, this cell type appears to be a critical contributor to neurodegeneration. Future work will focus on demonstrating the consequences of iron loading of microglia in vivo and identifying those factors that trigger neuronal death. Data already collected in this direction by Ryan et al. using a genome-wide CRISPR screen show that both established ferroptose regulators such as ACSL4 and a new factor, SEC24B, appear to be able to trigger cell death. SEC24B is a regulator of COPII-mediated protein transport from the endoplasmic reticulum to the Golgi apparatus. Silencing SEC24B rendered the cells resistant to ferroptotic cell death after treatment with iron. In doing so, the authors found that SEC24B is significantly upregulated in several neurodegenerative diseases, including ALS, multiple system atrophy, frontotemporal lobar degeneration, and Alzheimer's disease.
Therapeutically, elimination of iron, for example using iron chelators (deferiprone), is difficult because of the risk of further reduction of dopamine in PD patients. Tyrosine hydroxylase, the crucial enzyme for dopamine synthesis, works in an iron-dependent manner. Therefore, substances that inhibit ferroptosis are currently being tested in the first instance.
References:
Kenkhuis B, Bush AI, Ayton S (2023) How iron can drive neurodegeneration. Trends in Neurosciences 46:333
Ryan SK, Zelic M, Han Y, ... , Ofengeim D, Hammond TR (2023) Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration. Nature Neuroscience 26:12
Image credit: iStock/Jian Fan