Molecular sensors for the decoding of homeostasis disruptions in the retinal pigment epithelium: towards the understanding of retinal degenerative diseases

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Abstract

The significance of the selective enrichment in omega-3 essential fatty acids DHA, docosahexaenoic acid) in photoreceptor cells has remained, until recently, incompletely understood. We contributed to the discovery of a docosanoid synthesized from DHA by 15-lipoxygenase-1, which we dubbed neuroprotectin D1 (NPD1: 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic acid). NPD1 is promptly made on demand when homeostasis is at stake, as in oxidative stress, proteostasis dysfunctions and in early stages of neural injury, ischemia-reperfusion or neurodegenerations. Thus NPD1 is a protective sentinel, one of the very first defenses activated when cell homeostasis is threatened. The availability of anti-apoptotic BCL-2 proteins is positively modulated by NPD1, whereas pro-apoptotic BCL-2 proteins are negatively regulated, as is activated microglia. Neurodegenerative diseases, in addition to enhancing oxidative stress, disrupt the proteostasis network and leads to a cellular inability to scavenge structurally damaged abnormal proteins. The RPE cell response cascade potentiates disruptors of homeostasis through multiple checkpoints and signaling networks. NPD1, a key component of this response and of the lipidomic signature, targets neuroinflammatory signaling and proteostasis and in turn promotes homeostatic regulation of the transcription of key genes that in turn act as molecular decoders of input, and thus results in cell survival. (Supported by NIH: NINDS R01 NS046741, NEI R01 EY005121)

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