Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis.

Abstract

Dysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and occurs in both MS patients and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Divalent Metal Transporter1, a major iron importer in cells, is stimulated by signaling of Dexras1, a small G protein member of the Ras family. Dexras1 is activated by S-nitrosylation by nitric oxide (NO) produced by either inducible nitric oxide synthase in activated microglia/macrophages or neuronal nitric oxide synthase in neurons. Here we show Dexras1 exacerbates oxidative stress-induced neurodegeneration in experimental optic neuritis, an inflammatory demyelinating optic nerve condition that occurs in MS and EAE. Dexras1 deletion, as well as treatment with the iron chelator deferiprone, preserves vision and attenuates retinal ganglion cell (RGC) and axonal loss during EAE optic neuritis. These results suggest that iron entry triggered by NO-activated Dexras1 signaling is a potential mechanism of neuronal death in experimental optic neuritis. The current data suggest modulation of Dexras1 signaling and iron chelation are potential novel treatment strategies for optic neuritis and MS, and possibly other optic neuropathies as well.

• Authors: Reas S Khan, Bailey Baumann, Kimberly Dine, Ying Song, Joshua L Dunaief, Sangwon F Kim, Kenneth S Shindler
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 11664 (08 12 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31406150 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chelating Agents
• Deferiprone
• Nitric Oxide
• Iron
• Rasd1 protein, mouse
• ras Proteins

Topics

• Animals
• Chelating Agents (administration & dosage)
• Deferiprone (administration & dosage)
• Encephalomyelitis, Autoimmune, Experimental (complications, pathology)
• Female
• Humans
• Iron (metabolism)
• Mice
• Mice, Knockout
• Multiple Sclerosis (complications, pathology)
• Nitric Oxide (metabolism)
• Optic Neuritis (etiology, pathology, prevention & control)
• Oxidative Stress (drug effects, genetics)
• Signal Transduction (drug effects, genetics)
• ras Proteins (genetics, metabolism)