New ALS link: stem cell motor neurons undergo ferroptosis
A new study provides insight on the link between ferroptosis and ALS
I want to direct you to an excellent recent publication from Professor Wan Seok Yang and his team at St. John’s University.
Mouse embryonic stem-cell-derived motor neurons are susceptible to ferroptosis — PubMed
Wan did his postdoctoral training in my lab some years, so I know him well. In his new paper, he reports that mouse motor neurons generated in the laboratory are sensitive to ferroptosis, a form of iron-dependent cell death that we discovered and named in my lab a decade ago.
Wan and his team used a mouse embryonic stem cell line (named iNIL) to generate motor neurons in the laboratory, using established methods, and then tested whether these motor neurons were sensitive to ferroptosis, which has been previously linked to a variety of neurodegenerative diseases.
One common way to induce ferroptosis in the laboratory is to treat with an inhibitor of system xc-, which is a cell surface protein complex that imports the dimeric form of the amino acid cysteine, which helps to dampen ferroptosis.
However, when Wan and his team treated their motor neurons with an inhibitor of this system, they found no effect. Moreover, they found that these motor neurons don’t contain this complex.
This was somewhat surprising, as the neurotransmitter glutamate has been shown to inhibit this cysteine uptake mechanism as part of its toxic effect on some neurons, and motor neuron diseases are linked to glutamate toxicity.
However, Wan’s result suggests that glutamate toxicity in motor neurons is not due to depleting cysteine, but rather due to other effects of glutamate, such as its interaction with glutamate receptors, as shown in the image below.
However, when Wan’s team tested another way of triggering ferroptosis — inhibiting the lipid repair enzyme GPX4 — they found that did indeed trigger ferroptosis in these motor neurons. GPX4 normally restrains ferroptosis by repairing damage to lipids in cell membranes, and loss of this repair mechanism allows that damage to accumulate unchecked.
They tested whether an SOD1 mutant, which is an inherited mutation that can trigger the motor neuron disease known as amyotrophic lateral sclerosis (ALS), could change sensitivity to ferroptosis — it did not. In these motor neurons, this ALS-causing mutation did not sensitize to ferroptosis. That seemed to suggest ALS is not directly linked to ferroptosis.
However, they found that edaravone, a clinically used drug to treat ALS, did indeed prevent ferroptosis in these motor neurons, when it was triggered by inhibiting GPX4. This suggests that the protective mechanism of edaravone in patients could be at least in part by blocking ferroptosis.
In summary, the new paper suggests that motor neurons can undergo ferroptosis in response to loss of the GPX4, but not by cysteine deprivation or glutamate toxicity, and that drugs that prevent ferroptosis triggered by loss of GPX4 could potentially help ALS patients. It seems that in motor neurons, the ALS-linked SOD1 mutant doesn’t trigger or drive ferroptosis, but perhaps acts in other cell types.
Congratulations to Wan and his team for an excellent paper that sheds new light on the potential link between ferroptosis and ALS!
