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Review
. 2020 Dec 17;27(12):1456-1471.
doi: 10.1016/j.chembiol.2020.10.010. Epub 2020 Nov 10.

Using the Oxytosis/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases

Pamela Maher  1 , Antonio Currais  2 , David Schubert  2
Affiliations
Review

Using the Oxytosis/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases

Pamela Maher et al. Cell Chem Biol. .

Abstract

Oxytosis was first described over 30 years ago in nerve cells as a non-excitotoxic pathway for glutamate-induced cell death. The key steps of oxytosis, including glutathione depletion, lipoxygenase activation, reactive oxygen species accumulation, and calcium influx, were identified using a combination of chemical and genetic tools. A pathway with the same characteristics as oxytosis was identified in transformed fibroblasts in 2012 and named ferroptosis. Importantly, the pathophysiological changes seen in oxytosis and ferroptosis are also observed in multiple neurodegenerative diseases as well as in the aging brain. This led to the hypothesis that this pathway could be used as a screening tool to identify novel drug candidates for the treatment of multiple age-associated neurological disorders, including Alzheimer's disease (AD). Using this approach, we have identified several AD drug candidates, one of which is now in clinical trials, as well as new target pathways for AD.

Keywords: calcium; glutamate toxicity; glutathione; glutathione peroxidase 4; lipoxygenases; mitochondria; oxidative stress.

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Conflict of interest statement

Declaration of Interests D.S. was an unpaid advisor for Abrexa Pharmaceuticals, a company working on the development of J147 for AD therapy. The Salk Institute holds the patents for CMS121 (US9744164) and J147 (US8779002).

Figures

Figure 1:
Figure 1:
Time line of key discoveries in oxytosis/ferroptosis.
Figure 2:
Figure 2:
Time course of major pathophysiological changes that occur during oxytosis/ferroptosis.
Figure 3:
Figure 3:
AD drug discovery pipeline using oxytosis/ferroptosis as the primary screen.
Figure 4:
Figure 4:
Genesis of AD drug candidates based on oxytosis/ferroptosis as the primary screen.
Figure 5:
Figure 5:
Our chemical biology approach targeting oxytosis/ferroptosis.
See this image and copyright information in PMC

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