DHA Signaling
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DHA Signaling

The cell membranes do not simply serve as barriers to separate the inside of the cell from the outside or to delineate different intracellular compartments. These membranes also serve as a platform for cell signaling by allowing specific sets of proteins to interact. Phospholipids are major structural constituents of the cell membranes. In the cell membranes of neurons, the two most prevalent Phospholipids include PC (Phosphatidylcholine) and PS (Phosphatidylserine). When cell membranes are stimulated by cell signaling activity, enzymes (called Phospholipases) free lipid messengers from these reservoirs. The lipid messengers then regulate and interact with other signaling cascades to contribute to the development, differentiation, function protection, and repair of the nervous system. Some of these messengers are derived from essential fatty acids contained in Phospholipids. One of these essential fatty acids is DHA (Docosahexaenoic Acid). DHA, a member of the Omega-3 family of Essential Fatty Acids, is 22 carbons long and has 6 double bonds with the n-3 configuration. It is a major component of fish oil and marine algae. Diet-supplied DHA or its precursor, Alpha-Linolenic acid (18:3), are initially taken up by the liver and then distributed through blood lipoproteins to meet the needs of organs. DHA is most highly concentrated in Photoreceptors, Brain, and Retinal Synapses and displays beneficial actions in Neuronal development, Cancer, and Inflammatory Diseases (Ref.1 & 2).

In neuronal membranes, DHA accumulates in membrane Phospholipids, particularly in Aminophospholipids, Phosphatidylethanolamine, PI (Phosphatidylinositol) and PS (Phosphatidylserine). Stimulation or injury triggers the rapid release of DHA. DHA play an important role in Neuronal survival by modulating the PS level and by stimulating NPD1 (Neuroprotectin-D1) formation. DHA modulate the PS levels in vivo and in vitro. The increase of PS concentration by DHA promotes the interaction of the PH domain of Akt with the plasma membrane, facilitating translocation and phosphorylation of Akt. Membrane translocation is an event that is prerequisite for the full activation of Akt by enabling successive phosphorylation at Thr-308 and Ser-473 with kinases such as protein kinase PDK-1  (3-Phosphoinositide-dependent Protein Kinase-1). PDK-1, which phosphorylates Akt is activated by PIP3 (Phosphatidylinositol 3,4,5-trisphosphate), which is further activated by PI3K  (Phosphatidylinositde-3-Kinase). Growth Factor Receptor activation by Growth Factors creates phosphotyrosine containing binding sites for the SH2 (Src Homology-2) domains of the p85 regulatory subunit of PI3K which results in catalytic p110 subunit phosphorylation of PIP2 (Phosphatidylinositol (4,5) Bisphosphate) and formation of the Akt activator, PIP3. Fully active Akt is then released from Plasma membrane to the cytoplasm by PTEN  dephosphorylation of PIP3 at the D3 position of the inositol ring reverts the PI product back to PIP2. As the cascade continues, Akt then phosphorylates and inactivates both Alpha and Beta cytosolic forms of GSK3 (Glycogen Synthase Kinase-3), pro-apoptotic regulators like BAD  (BCL2 Associated Death Promoter), and also modulates downstream TOR (Target of Rapamycin) regulation of translation, and NRF2/ARE (NFE2 Related Factor-2) and FkhR (Forkhead In Rhabdomyosarcoma) family member regulation of transcription. GSK3, once inactivated cannot activate proteins like Tau and ABeta (Amyloid Beta), which take part in neuronal death. Inactivation of pro-apoptotic regulators like BAD  causes inactivation of Caspases and activation of anti-apoptotic regulators like Bcl2  (B-Cell CLL/Lymphoma-2) and BclXL (Bcl2 Related Protein Long Isoform) which ultimately promotes Cell survival. Akt also inactivates Caspase9  and leads to cell survival. Growth Factors like Insulin-mediated Akt activation leads to upregulation of IDE (Insulin Degrading Enzyme), a metalloprotease enzyme responsible for Insulin degradation, presumably as a negative feedback control mechanism.IDE not only plays a major role in Insulin catabolism, but also mediates ABeta degradation, which is a major activator of Apoptosis. The capacity to concentrate membrane PS by DHA is an important determinant for modulating survival signaling. The cell survival inadequately supported, especially under stressed conditions, have a significant implication in neurological deficit often observed in n-3 fatty acid deficiency (Ref. 3, 4 & 5).

Besides regulating the PS level in the membrane, DHA also stimulate NPD1 formation and is required for RPE (Retinal Pigment Epithelium cell) functional integrity. NPD1 is the first identified neuroprotective derivative of DHA. DHA is taken up from the bloodstream by RPE cells through the Choriocapillaris. Human RPE cells synthesize this stereospecific mediator NPD1, which is also known as 10,17-S-DHA, through DHA oxygenation that involves PLA2 (Phospholipases-A2)  followed by 15-LOX (15- Lipoxygenase)-like activity. PLA2 (which forms of this enzyme are involved is not yet entirely known), activated by Growth Factor Receptors like PEDFR (Pigment-Epithelium-Derived Factor Receptor), cleave specific DHA-phospholipids, leading to the synthesis of NPD1. Formation of NPD1 from DHA occurs via intermediates like 17S-HpDHA and 16S,17S-DHA Epoxide. The agonists of NPD1 synthesis include Neurotrophic Growth factors such as PEDF  (Pigment-Epithelium-Derived Factor), oxidative stress mediated by H2O2, TNF-Alpha  (Tumor Necrosis Factor-Alpha) and Serum deprivation, Brain Ischemia-reperfusion, IL-1Beta  (Interleukin-1-Beta), the Ca2C Ionophore A23187, A2E (N-Retinylidene-N-Retinyl Ethanolamine), the Amyloid-Beta Peptide ABeta40, and sAPP-Alpha (Soluble Amyloid Precursor Protein-Alpha). Once formed, NPD1 then probably works through a receptor yet to be elucidated (Ref. 3, 6 & 7).

NPD1 inhibits oxidative-stress-mediated Proinflammatory gene induction and Apoptosis, and consequently promotes RPE cell survival. NPD1 promotes differential modification in the expression of Bcl2 family proteins, upregulating protective Bcl2 proteins (Bcl2BclXL  and BFL1/A1) and attenuating the expression of the proteins that challenge cell survival (e.g. BAX  (Bcl2 Associated-X Protein), BADBID  (BH3 Interacting Domain Death Agonist) and BIK(Bcl2-Interacting Killer)). NPD1 is believed to regulate expression of the genes encoding death repressors and effectors of the Bcl2  family of proteins. However, translational or post-translational events might also integrate a concerted responsive machinery to counteract oxidative stress. The precise molecular mechanisms involved remain to be defined, and exploration of these events will provide important insight into regulatory survival signaling. Bcl2 family proteins regulate apoptotic signaling at the level of mitochondria and the endoplasmic reticulum. As a consequence, CytoC  (Cytochrome-C) is released from mitochondria and effector Caspase3  is activated via APAF1  (Apoptotic Peptidase Activating Factor-1) and Caspase9. NPD1 also mediate opposite changes from those elicited by the Amyloid Beta peptide ABeta42. This peptide enhances expression of genes encoding the Cytokines CEX1 (Cytokine Exodus Protein-1), IL-1BetaTNF-Alpha  (Tumor Necrosis Factor-Alpha) and COX2  (Cyclooxygenase-2), in addition to the TNF-Alpha  -inducible pro-inflammatory element B94 and the pro-apoptotic BIKand BAX  proteins. CEX1 is a marker for inflammatory and oxidative stress responses, and B94 is a TNF-Alpha-inducible pro-inflammatory element. Expression of these and other Pro-inflammatory proteins finally lead to Cell Survival (Ref. 8 & 9). Because photoreceptors are progressively impaired after RPE cell damage in retinal degenerative diseases, understanding of how these signals contribute to retinal cell survival may lead to the development of new therapeutic strategies. Moreover, NPD1 bioactivity demonstrates that DHA is not only a target of lipid peroxidation, but rather is the precursor to a neuroprotective signaling response to Ischemia-reperfusion, thus opening newer avenues of therapeutic exploration in stroke, neurotrauma, spinal cord injury, and neurodegenerative diseases, aiming to up-regulate this novel cell-survival signaling. DHA deprivation results in neurological defects, primarily in the memory, visual and sensory systems. Furthermore, dietary supplementation with DHA is beneficial in various psychiatric disorders, including Alzheimer’s disease, Attention deficit hyperactivity disorder, Autism, Schizophrenia, Anxiety, Bipolar Disorder and Depression (Ref.1, 10 & 11).