Nerve growth factor

Nerve growth factor (NGF) is a small secreted is_associated_with::protein that is important for the growth, maintenance, and survival of certain target is_associated_with::neurons (nerve cells). It also functions as a signaling molecule. It is perhaps the prototypical is_associated_with::growth factor, in that it is one of the first to be described. While "nerve growth factor" refers to a single factor, "nerve growth factors" refers to a family of factors also known as is_associated_with::neurotrophins. Other members of the neurotrophin family that are well recognized include Brain-Derived Neurotrophic Factor (is_associated_with::BDNF), is_associated_with::Neurotrophin-3 (NT-3), and Neurotrophin 4/5 (NT-4/5).

Function and mechanism of action
NGF is critical for the survival and maintenance of sympathetic and is_associated_with::sensory neurons, as they will undergo is_associated_with::apoptosis in the absence of the protein. Nerve growth factor causes axonal growth. Studies have shown that it causes axonal branching and a bit of elongation. NGF binds with at least two classes of receptors: the p75 LNGFR (for "is_associated_with::low-affinity nerve growth factor receptor") neurotrophin receptor (p75(NTR)) and TrkA, a transmembrane tyrosine kinase. Both are associated with neurodegenerative disorders.

NGF binds to high-affinity is_associated_with::tropomyosin receptor kinase A (TrkA). TrkA dimerizes and autophosphorylates its tyrosine kinase segment, which leads to the activation of is_associated_with::PI 3-kinase, ras, and PLC signaling pathways. Alternatively, the p75NTR receptor can form a heterodimer with TrkA which has higher affinity and specificity for NGF.

There is evidence that NGF circulates throughout the entire body and is important for maintaining is_associated_with::homeostasis.

Major neuron-survival pathways mediated by NGF signaling
Binding interaction between NGF and the TrkA receptor facilitates receptor dimerization and tyrosine residue phosphorylation of the cytoplasmic tail by adjacent Trk receptors. Trk receptor phosphorylation sites operate as Shc adaptor protein docking sites, which undergo phosphorylation by the TrkA receptor Once the cytoplasmic is_associated_with::adaptor protein (Shc) is phosphorylated by the receptor cytoplasmic tail, cell survival is initiated through several intracellular pathways.

One major pathway leads to the activation of the serine/threonine kinase, is_associated_with::Akt. This pathway begins with the Trk receptor complex-recruitment of a second adaptor protein called growth factor-receptor bound protein-2 (is_associated_with::Grb2) along with a docking protein called Grb2-associated Binder-1 (is_associated_with::GAB1). Subsequently, phosphatidylinositol-3 kinase (is_associated_with::PI3K) is activated, resulting in Akt kinase activation. Study results have shown that blocking PI3K or Akt activity results in death of sympathetic neurons in culture, regardless of NGF presence. However if either kinase is constitutively active, neurons survive even without NGF.

A second pathway contributing to cell survival occurs through activation of the mitogen-activated protein kinase (is_associated_with::MAPK) kinase. In this pathway, recruitment of a guanine nucleotide exchange factor by the adaptor and docking proteins leads to activation of a membrane-associated G-protein known as Ras. The guanine nucleotide exchange factor mediates Ras activation through the GDP-GTP exchange process. The active Ras protein phosphorylates several proteins, along with the serine/ threonine kinase, is_associated_with::Raf. Raf, in turn activates the MAPK cascade to facilitate is_associated_with::ribosomal s6 kinase(RSK) activation and transcriptional regulation.

Both Akt and RSK, components of the PI3K-Akt and MAPK pathways respectively, act to phosphorylate the cyclic AMP response element binding protein (is_associated_with::CREB) transcription factor. Phosphorylated CREB translocates into the nucleus and mediates increased expression of anti-apoptotic proteins, thus promoting NGF-mediated cell survival. However, in the absence of NGF, the expression of pro-apoptotic proteins is increased when the activation of cell death-promoting transcription factors such as is_associated_with::c-Jun are not suppressed by the aforementioned NGF-mediated cell survival pathways.

Roles of ProNGF in the survival and death of neurons
There is also evidence that shows that the precursor to NGF, pro-NGF, may also play important roles due to its abundance. These include apoptotic and neurotrophic properties.

Pro-NGF is the uncleaved, precursor protein form of the active peptide form of NGF. The Pro-NGF precursor is biologically inactive, as it does not undergo post-transcriptional modification. Pro-NGF acts with a coreceptor, sortilin, to bind the 75kD neurotrophin receptor known as is_associated_with::P75NTR (a tumor necrosis factor family member). High affinity binding between Pro-NGF, sortilin, and p75NTR can result in either survival or is_associated_with::programmed cell death (PCD). Study results indicate that superior cervical ganglia neurons that express both p75NTR and TrkA die when treated with proNGF, where as 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 the p75NTR cytoplasmic tail. Survival occurs when recruited cytoplasmic adaptor proteins facilitate signal transduction through tumor necrosis factor receptor members such as is_associated_with::TRAF6, which results in the release of nuclear factor κB (is_associated_with::NF-κB) transcription activator. NF-κB regulates nuclear gene transcription to promote cell survival. Alternatively, PCD occurs when TRAF6 and neurotrophin receptor interacting factor (NRIF) are both recruited to activate is_associated_with::c-Jun N-terminal kinase (JNK); which phosphorylates c-Jun. The activated transcription factor c-Jun regulates nuclear transcription to increase pro-apoptotic gene transcription.

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 ovulate when semen from on-schedule or “spontaneous” ovulators, such as cattle is used. Its significance in humans is currently unknown. It was previously dubbed ovulation-inducing factor (OIF) in semen before its final identification as β-NGF in 2012.

Structure
The structure of NGF was first solved by is_associated_with::X-ray crystallography and published in 1991 by McDonald et al. in Nature. NGF forms a is_associated_with::cystine knot structure made up of is_associated_with::beta strands twisted around each other and linked by is_associated_with::disulfide bonds. Most structures are dimeric. At the time this structure was solved, this fold had never been seen before. Hence NGF is the founding member of the nerve growth factor family of structurally conserved proteins.

History
is_associated_with::Rita Levi-Montalcini and Stanley Cohen discovered NGF in the 1950s while faculty members at is_associated_with::Washington University in St Louis. However, its discovery, along with the discovery of other neurotrophins, was not widely recognized until 1986, when it won the is_associated_with::Nobel Prize in Physiology or Medicine.

Studies in 1971 determined the is_associated_with::primary structure of NGF. This eventually led to the discovery of the NGF gene.

NGF is abundant in seminal plasma. Recent studies have found that it induces ovulation in some mammals.

Clinical significance
NGF prevents or reduces neuronal degeneration in animal models of is_associated_with::neurodegenerative diseases and these encouraging results in animals have led to several clinical trials in humans. NGF has also been shown to promote peripheral nerve regeneration in rats. The expression of NGF is increased in inflammatory diseases where it suppresses inflammation. Also, NGF appears to promote myelin repair. Hence NGF may be useful for the treatment of is_associated_with::multiple sclerosis. NGF could also be involved in various is_associated_with::psychiatric disorders, such as is_associated_with::dementia, depression, is_associated_with::schizophrenia, is_associated_with::autism, is_associated_with::Rett syndrome, is_associated_with::anorexia nervosa, and is_associated_with::bulimia nervosa. Dysregulation of NGF signaling has also been linked to is_associated_with::Alzheimer's disease.

Neurotrophins, including NGF, have been shown to affect many areas of the brain, including areas that are related to Rett syndrome, is_associated_with::bipolar disorder, and Alzheimer’s disease. Stress and/or anxiety are usually a precipitating factor in these disorders and affects levels of NGF, leading to impaired cognitive functioning.

This impaired cognitive functioning can be seen in patients with is_associated_with::Schizophrenia. In treatment of schizophrenia, NGF levels are increased in patients using is_associated_with::atypical antipsychotic medication, but not in patients using is_associated_with::typical antipsychotic medications. Patients using atypical medications usually report improved cognitive performance compared to those using typical antipsychotics. In addition, these higher NGF levels from the atypical antipsychotic medications lead to a reduction in negative symptoms of Schizophrenia.

Nerve Growth Factor has been shown to restore learning ability in rats recovering from induced alcoholism

Rett syndrome and is_associated_with::Autism often show similar signs early in life, such as slowing development and intellectual disability. One distinguishing factor is that low levels of NGF have been found in the cerebral spinal fluid of those with Rett Syndrome compared to children with Autism who have relatively normal to high levels Pharmaceutical therapies with NGF-like activity can be effective in treating Rett syndrome, including better motor and cortical functioning as well as increased social communication.

Impairment of neuroplasticity and altered levels of neuro-trophins are involved in Bipolar Disorder. NGF has been found to be decreased overall in Bipolar Disorder patients. More specifically, while in a manic state NGF is especially low. This leads to elevated or irritable mood with increased energy and decreased need for sleep while in a manic state. This decreased NGF may serve as a biological marker when assessing the present state of a Bipolar Disorder patient. When Bipolar Disorder patients were treated with lithium, their NGF concentrations increased in the frontal cortex, limbic forebrain, hippocampus, and amygdala.

An increase in cortical and subcortical NGF has been found in patients with Alzheimer’s disease. Alzheimer’s is a neurodegenerative disease with which dysregulation of NGF signaling has also been linked, causing impaired retrograde transport of NGF to certain areas of the brain. This impairment may be caused by an atypical production or use of receptors in the brain. Stimulating NGF receptors via NGF infusion has been shown to increase blood flow and verbal episodic memory. These improvements have been longer lasting than other treatments for Alzheimer’s.

Also, NGF has been shown to play a role in number is_associated_with::cardiovascular diseases, such as coronary is_associated_with::atherosclerosis, is_associated_with::obesity, type 2 is_associated_with::diabetes, and metabolic syndrome. Reduced plasma levels of NGF and BDNF have been associated with acute coronary syndromes and metabolic syndromes. NGF is known to have insulinotropic, angiogenic, and antioxidant properties. NGF suppresses food intake.

NGF has also been shown to accelerate wound healing. There is evidence that it could be useful in the treatment of skin ulcers and cornea ulcers.

In some gynecological diseases, an elevated is_associated_with::prostaglandin E2 is thought to stimulate production of NGF which contributes to the perception of pain and increased inflammation in is_associated_with::endometriosis.

Monoclonal antibodies against NGF have been used in clinical trials to modulate pain. One of these is is_associated_with::Tanezumab.

Cultural significance
In 2005, is_associated_with::Enzo Emanuele and coworkers at is_associated_with::University of Pavia found that nerve growth factor (NGF) has high levels when people first fall in is_associated_with::love, but these levels return to as they were after one year. To be specific, four neurotrophin levels, i.e., NGF, BDNF, NT-3, and NT-4, of 58 subjects who had recently fallen in love were compared with levels in a control group who were either single or already engaged in a long-term relationship. The results showed that NGF levels were significantly higher in the subjects in love than as compared to either of the control groups. Nerve growth factor may contribute to increased longevity and mental capacity. is_associated_with::Centenarian is_associated_with::Rita Levi-Montalcini took a daily solution in the form of eye drops, and has stated that her brain is more active now than it was four decades ago. In 2014, Sundaravadivel Balasubramanian and coworkers at is_associated_with::Medical University of South Carolina showed that NGF level is elevated in people who performed a single session 20 minute Yoga Breathing involving Om chanting and Thirumoolar Pranayama, when compared to Control group.

Interactions
Nerve growth factor has been shown to interact with is_associated_with::TrkA and is_associated_with::Low affinity nerve growth factor receptor.