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.
Highlights
Www.nature.com/scientificreports within tissues leads to generation of free radicals, resulting in oxidative stress, which has been implicated in the pathogenesis of multiple sclerosis (MS), potentially contributing to both demyelination and axonal damage[11]
Dexras[1] is a small G protein activated by nitric oxide (NO), which can be produced by inducible NO synthase in activated microglia/macrophages or by neuronal NO synthase in neurons[15], two cell types intimately involved in optic neuritis
To evaluate whether EAE induction has a direct effect on proteins involved in Dexras[1] signaling, one of the pathways that induces iron influx into the cells, proteins isolated from optic nerves and retina from control and EAE mice (N = 4 mice/group) were subjected to Western blot analysis and probed for detection of inducible NO synthase (iNOS), Dexras[1], S-nitrosylated Dexras[1] (Dexras1-SNO), and GAPDH as a housekeeping marker
Summary
Www.nature.com/scientificreports within tissues leads to generation of free radicals, resulting in oxidative stress, which has been implicated in the pathogenesis of MS, potentially contributing to both demyelination and axonal damage[11]. Several studies have suggested that iron chelation, by sequestering circulating free iron and reducing free radical toxicity, could be a viable strategy to reduce spinal cord disease in EAE12–14, effects on RGCs and optic nerve dysfunction were not reported, and the mechanisms by which free iron enters neurons and mediates neuronal damage in EAE are not fully understood. While increased iron levels have been noted in MS patients, and iron chelation reduces spinal cord disease in EAE, the potential role of iron and iron uptake in optic neuritis, and in RGCs, is not clear. In the present study, we investigated whether Dexras[1] deletion or iron chelation reduces RGC damage in EAE by reducing neurotoxicity
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