Neuroprotectin D1 Induces Dephosphorylation of Bcl-x(L) in a PP2A-dependent Manner during Oxidative Stress and Promotes Retinal Pigment Epithelial Cell Survival

Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2010; 285(24):18301-8. DOI: 10.1074/jbc.M109.095232
Source: PubMed


Retinal pigment epithelial (RPE) cell integrity is critical for the survival of photoreceptor cells. Bcl-xL is a major anti-apoptotic Bcl-2 protein required for RPE cell survival, and phosphorylation of Bcl-xL at residue Ser-62 renders this protein pro-apoptotic. In this study, we identify serine/threonine protein phosphatase 2A
(PP2A) as a key regulator of Bcl-xL phosphorylation at residue Ser-62 in ARPE-19 cells, a spontaneously arising RPE cell line in which Bcl-xL is highly expressed. We found that either PP2A inhibitor okadaic acid or depletion of catalytic subunit α of PP2A (PP2A/Cα)
by small interfering RNA enhanced Bcl-xL phosphorylation when activated with hydrogen peroxide and tumor necrosis factor α-induced oxidative stress. Disruption of
PP2A/Cα exacerbated oxidative stress-induced apoptosis. PP2A/Cα colocalized and interacted with S62Bcl-xL in cells stressed with H2O2/tumor necrosis factor α. By contrast, the omega-3 fatty acid docosahexaenoic acid derivative, neuroprotectin D1 (NPD1), a
potent activator of survival signaling, down-regulated oxidative stress-induced phosphorylation of Bcl-xL by increasing protein phosphatase activity. NPD1 also attenuated the oxidative stress-induced apoptosis by knockdown of PP2A/Cα
and increased the association of PP2A/Cα with S62Bcl-xL as well as total Bcl-xL. NPD1 also enhanced the heterodimerization of Bcl-xL with its counterpart, pro-apoptotic protein Bax. Thus, NPD1 modulates the activation of this Bcl-2 family protein by dephosphorylating
in a PP2A-dependent manner, suggesting a coordinated, NPD1-mediated regulation of cell survival in response to oxidative stress.

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    • "Moreover, omega-3 essential fatty acid-rich diets are associated with a trend in reduced risk for MCI and with MCI conversion to AD, whereas DHA has been shown to be beneficial in transgenic AD models [8], [10], [11], [16], [50]. The 15-lipoxygenase-1- (15-LOX-1) DHA-derived NPD1 displays neuroprotective bioactivity in brain and retinal cells against various insults, including oxidative injury, ischemia-reperfusion and inflammation [9], [17], [18], [51]–[53]. Both AD brain [9] and the 3xTg-AD mouse exhibit reductions in DHA and NPD1 (Figure 1). "
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    ABSTRACT: Neuroprotectin D1 (NPD1) is a stereoselective mediator derived from the omega-3 essential fatty acid docosahexaenoic acid (DHA) with potent inflammatory resolving and neuroprotective bioactivity. NPD1 reduces Aβ42 peptide release from aging human brain cells and is severely depleted in Alzheimer's disease (AD) brain. Here we further characterize the mechanism of NPD1's neurogenic actions using 3xTg-AD mouse models and human neuronal-glial (HNG) cells in primary culture, either challenged with Aβ42 oligomeric peptide, or transfected with beta amyloid precursor protein (βAPP)sw (Swedish double mutation APP695sw, K595N-M596L). We also show that NPD1 downregulates Aβ42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-α-inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses Aβ42 peptide shedding by down-regulating β-secretase-1 (BACE1) while activating the α-secretase ADAM10 and up-regulating sAPPα, thus shifting the cleavage of βAPP holoenzyme from an amyloidogenic into the non-amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the irreversible PPARγ antagonist GW9662, and overexpressing PPARγ suggests that the NPD1-mediated down-regulation of BACE1 and Aβ42 peptide release is PPARγ-dependent. In conclusion, NPD1 bioactivity potently down regulates inflammatory signaling, amyloidogenic APP cleavage and apoptosis, underscoring the potential of this lipid mediator to rescue human brain cells in early stages of neurodegenerations.
    Full-text · Article · Jan 2011 · PLoS ONE

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