Abstract
Emerging strategies that center upon the mammalian target of rapamycin (mTOR) signaling for neurodegenerative disorders may bring effective treatment for a number of difficult disease entities. Here we show that erythropoietin (EPO), a novel agent for nervous system disorders, prevents apoptotic SH-SY5Y cell injury in an oxidative stress model of oxygen-glucose deprivation through phosphatidylinositol-3-kinase (PI 3-K)/protein kinase B (Akt) dependent activation of mTOR signaling and phosphorylation of the downstream pathways of p70 ribosomal S6 kinase (p70S6K), eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and proline rich Akt substrate 40 kDa (PRAS40). PRAS40 is an important regulatory component either alone or in conjunction with EPO signal transduction that can determine cell survival through apoptotic caspase 3 activation. EPO and the PI 3-K/Akt pathways control cell survival and mTOR activity through the inhibitory post-translational phosphorylation of PRAS40 that leads to subcellular binding of PRAS40 to the cytoplasmic docking protein 14-3-3. However, modulation and phosphorylation of PRAS40 is independent of other protective pathways of EPO that involve extracellular signal related kinase (ERK 1/2) and signal transducer and activator of transcription (STAT5). Our studies highlight EPO and PRAS40 signaling in the mTOR pathway as potential therapeutic strategies for development against degenerative disorders that lead to cell demise.
Highlights
Neurodegenerative disease leads to either severe disability or death for a significant proportion of the world’s population
We show that in a model of oxygen-glucose deprivation (OGD) that can lead to oxidative stress [45,46], EPO activates mammalian target of rapamycin (mTOR) signaling through PI 3-K/Akt pathways to phosphorylate p70 ribosomal S6 kinase (p70S6K) and 4E-binding protein 1 (4EBP1) that is necessary for protection in differentiated SH-SY5Y cells
Non-specific scrambled small interfering RNA (siRNA) during EPO treatment did not alter survival or DNA fragmentation when compared to EPO treatment and OGD exposure alone
Summary
Neurodegenerative disease leads to either severe disability or death for a significant proportion of the world’s population. Multiple factors may contribute to the onset and progression of neurodegenerative disease, oxidative stress is considered to be an important component in neurodegenerative disorders. Oxidative stress can lead to cognitive disorders [4,5,6], movement disorders [5,7,8], and neurovascular complications associated with metabolic disease [9,10,11]. Given that effective treatments for the majority of neurodegenerative disorders do not exist, new strategies that can offer protection in the nervous system during oxidative stress are of great interest [12,13]. More recent studies have demonstrated that EPO relies upon mammalian target of rapamycin (mTOR) signaling to modulate inflammatory cell survival [27,33], osteoblastogenesis, and osteoclastogenesis [34]
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