Ferroptosis in dopamine neurons

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Scott Dixon, Brent Stockwell (last author) and colleagues (Cell 149:1060–1072, May 2012; PubMed lists NIH extramural support). Bao Do Van, Flore Gouel, David Devos, Jean-Christophe Devedjian and colleagues in Lille (Neurobiology of Disease 94:169–178, 2016). Funders of the 2016 paper were not read.

What happened

• 2012. Searching for compounds that kill cancer cells carrying mutant RAS, Dixon et al. found that erastin triggers death that needs iron but not other metals. They named it ferroptosis. It differs from apoptosis, necrosis and autophagy. Erastin blocks the uptake of cystine, which starves the cell of its antioxidant glutathione, and the cell dies from iron-driven oxidation of fats. A small molecule, ferrostatin-1, blocked it, and also blocked glutamate-induced death in rat brain slices. The authors suggested blocking it might protect against neurodegeneration.
• 2016. Do Van et al. tested dopamine cells. Ferroptosis occurred in a human dopaminergic cell line (LUHMES), in brain slice cultures, and in the MPTP mouse model. They reported that it can be set off by activation of protein kinase C alpha (PKC), acting through MEK without RAS, which differs from the cancer-cell pathway. The authors proposed iron chelators, ferrostatin derivatives and PKC inhibitors as drug candidates; the abstract does not give effect sizes.

Why it moved us toward a cure

Raised nigral iron had been known since 1988 (landmark 128). Ferroptosis offered a precise route by which iron could kill dopamine neurons, and drugs that block it, not only iron chelators. It also set up a warning: the iron chelator deferiprone worsened early Parkinson's in FAIRPARK-II (landmark 67), so removing iron is not the same as blocking ferroptosis.

Outcome

Open. The 2016 work used cell and MPTP-mouse models. No ferroptosis-targeted drug trial in people with Parkinson's was found in this check. Later reports of ferroptosis markers in Parkinson's brain tissue turned up in a search but were not read or verified. Neither key paper has an erratum or retraction listed in Europe PMC (Dixon 2012 has two commentaries).

Sources

• Dixon et al., Cell 2012, DOI 10.1016/j.cell.2012.03.042, PubMed 22632970
• Do Van et al., Neurobiol Dis 2016, DOI 10.1016/j.nbd.2016.05.011, PubMed 27189756
• Not yet verified: evidence of ferroptosis in Parkinson's patient brain (search results seen, not read); independent replication of Do Van 2016; whether a ferroptosis-specific drug is in a Parkinson's trial (search was cursory); full texts.