Introduction:Structure:Function:Neuronal proliferation:Regulation of the immune system:Ovulation:Romantic love:Clinical significance:Non-regulation of NGF Signaling:Conclusion:(Nerve Growth Factor)Submitted by:Hafiz Muhammad Zeeshan RazaCIIT/FA-17/RBS-002/SWLBiosciences DepartmentCOMSATS INSTITUTE OF INFORMATION TECHNOLOGYSAHIWAL CAMPUSNerve growth factorIntroduction:Nerve growth factor(NGF) is aneurotrophic factorandneuropeptideprimarily involved in the regulation ofgrowth, maintenance, proliferation, and survival of certain targetneurons. It is perhaps the prototypicalgrowthfactor, in that it was one of the first to be described. Since it was first isolated by Nobel Laureates Rita Levi-MontalciniandStanley Cohenin 1956, numerous biological processes involving NGF have been identified,two of them being the survival ofpancreatic beta cellsand the regulation of theimmune system.Structure:NGF is initially in a 7S, 130-kDacomplex of 3 proteins - Alpha-NGF, Beta-NGF, and Gamma-NGF (2:1:2ratio) when expressed. This form of NGF is also referred to aspro NGF(NGF precursor). The gamma subunitof this complex acts as a serine protease, and cleaves the N-terminal of the beta subunit, thereby activating theprotein into functional NGF.Function:As its name suggests, NGF is involved primarily in the growth, as well as the maintenance, proliferation, andsurvival of nerve cells (neurons). In fact, NGF is critical for the survival and maintenance of sympatheticandsensory neurons, as they undergoapoptosisin its absence. However, several recent studies suggest thatNGF is also involved in pathways besides those regulating the life cycle of neurons.Neuronal proliferation:NGF can drive the expression of genes such asbcl-2by binding to the TrkA receptor, which stimulates theproliferation and survival of the target neuron.High affinity binding between pro NGF, sortilin, and p75NTR can result in either survival orprogrammed celldeath. Study results indicate that superior cervical ganglia neurons that express both p75NTR and TrkA diewhen treated with pro NGF, while NGF treatment of these same neurons results in survival and axonal growth.Survival and PCD mechanisms are mediated through adaptor protein binding to the death domain of thep75NTR cytoplasmic tail.Regulation of the immune system:NGF plays a critical role in the regulation of both innate and acquired immunity. In the processofinflammation, NGF is released in high concentrations bymast cells, and induces axonal outgrowth innearby nociceptive neurons. This leads to increased pain perception in areas under inflammation. In acquiredimmunity, NGF is produced by the Thymus as well asCD4+ T cell clones, inducing a cascade of maturationof T cells under infection. Ovulation:NGF is abundant in seminal plasma. Recent studies have found that it induces ovulation in some mammals e.g.“induced” ovulators, such as llamas. Surprisingly, research showed that these induced animals will also ovulatewhen semen from on-schedule or “spontaneous” ovulators, such as cattle is used. Its significance in humans isunknown. It was previously dubbed ovulation-inducing factor (OIF) in semen before it was identified as beta-NGF in 2012.Romantic love:NGF can indirectly stimulate the expression ofadrenocorticotrophic hormone(ACTH) in thehypothalamic-pituitary-adrenal axis(HPA) by increasingVasopressinsecretion. ACTH binds to theMC2receptorintheZona fasciculataof theadrenal cortex, and stimulates secretion of the stress hormonecortisol.This rapidincrease of cortisol in the blood plasma can induce feelings of euphoria, which may explain the initial "rush" offalling in love.Studies show that ACTH can in turn stimulate NGF secretion in both the cerebral cortex andthe hypothalamus. It is possible that this NGF-ACTH interaction may form a recursive cycle, maintaining the"feeling of love" for a certain length of time. Because NGF modulates nerve plasticity, neurogenesis, andaxonal outgrowth, this may form permanent memories associating the loved one with the feeling of love duringthe course of the cycle. However, it has been shown that cortisol, whose secretion is directly upregulated byACTH, shows inhibitory effects over NGF expression in the cerebral cortex.This may be the cause of theeventual deterioration of NGF levels after 12 months. It may also explain why plasma NGF levels weresignificantly lower in individuals who have maintained a long-lasting romantic relationship beyond 12 months,than those who weren't in a romantic relationship at all.Clinical significance:Nerve growth factor prevents or reduces neuronal degeneration in animal modelsofneurodegenerativediseases and these encouraging results in animals have led to several clinical trials inhumans.NGF promotes peripheral nerve regeneration in rats.The expression of NGF is increasedininflammatorydiseases where it suppresses inflammation.NGF appears to promote myelin repair.HenceNGF may be useful for the treatment ofmultiple sclerosis.NGF could also be involved in variouspsychiatricdisorders, such asdementia,depression,schizophrenia,autism,Rett syndrome,anorexia nervosa,andbulimia nervosa. Non-regulation of NGF Signaling:It has also been linked toAlzheimer's disease.Connective tissue cells genetically engineered to synthesizeand secrete NGF and implanted in patients'basal forebrainsreliably pumped out NGF, which enhanced thecells’ size and their ability to sprout new neural fibers. The treatment also rescued vulnerable cells, even if theyalready showed the trademark signs of Alzheimer’s pathology. In some patients, these beneficial effects lastedalmost 10 years after the treatment. Even patients who died responded positively to the therapy. Evenpathological cells with protein clumps in their cell bodies and surroundings extended their fibers toward theNGF source, maintained a healthy size and activated pro-survival signals that boosted their stress resilience.Two other patients received direct injections of modified viruses containing the NGF gene directly to theirbasal forebrains. This allowed the gene to express longer in the brain. Conclusion:An increase in cortical and subcortical NGF has