Nerve growth factor

Nerve growth factor (beta polypeptide)
Rendering of NGF from PDB 1SG1
Available structures PDB 1SG1, 1WWW, 2IFG
Identifiers
Symbols	NGF; Beta-NGF; HSAN5; MGC161426; MGC161428; NGFB
External IDs	OMIM: 162030 MGI: 97321 HomoloGene: 1876 GeneCards: NGF Gene
Gene Ontology Molecular function • signal transducer activity • receptor signaling protein activity • nerve growth factor receptor binding • growth factor activity Cellular component • extracellular region • extracellular region • extracellular space • endosome • endosome • Golgi lumen Biological process • activation of MAPKK activity • apoptosis • anti-apoptosis • inflammatory response • transmembrane receptor protein tyrosine kinase signaling pathway • activation of phospholipase C activity • small GTPase mediated signal transduction • Ras protein signal transduction • peripheral nervous system development • memory • positive regulation of cell proliferation • adult locomotory behavior • induction of apoptosis by extracellular signals • response to radiation • response to mechanical stimulus • response to organic cyclic compound • sensory perception of pain • neuron projection development • nerve growth factor processing • response to lipopolysaccharide • response to drug • response to peptide hormone stimulus • negative regulation of neuron apoptosis • regulation of neuron differentiation • positive regulation of axon extension • negative regulation of cell cycle • regulation of neurotransmitter secretion • nerve growth factor receptor signaling pathway • phosphatidylinositol-mediated signaling • regulation of axonogenesis • positive regulation of axonogenesis • response to glucocorticoid stimulus • response to electrical stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4803	18049
Ensembl	ENSG00000134259	ENSMUSG00000027859
UniProt	P01138	Q6LDU8
RefSeq (mRNA)	NM_002506.2	NM_013609
RefSeq (protein)	NP_002497.2	NP_038637
Location (UCSC)	Chr 1: 115.83 – 115.88 Mb	Chr 3: 102.27 – 102.32 Mb
PubMed search	[1]	[2]

Nerve growth factor (NGF) is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons (nerve cells). It also functions as a signaling molecule.^[1][2] It is perhaps the prototypical growth factor, in that it is one of the first to be described. While "nerve growth factor" refers to a single factor,^[3] "nerve growth factors" refers to a family of factors also known as neurotrophins.^[4] Other members of the neurotrophin family that are well recognized include Brain-Derived Neurotrophic Factor (BDNF), 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 sensory neurons. Without it, these neurons undergo apoptosis.^[5] Nerve growth factor causes axonal growth. Studies have shown that it causes axonal branching and a bit of elongation.^[6] NGF binds with at least two classes of receptors: the p75 LNGFR (for "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 tyrosine kinase receptor TrkA. This phosphorylates TrkA, which leads to the activation of PI 3 Kinase, ras, and PLC signaling pathways.

There is evidence that NGF circulates throughout the entire body and is important for maintaining homeostasis.^[7]

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.^[8]

Structure

The structure of NGF was first solved by X-ray crystallography and published in 1991 by McDonald et al in Nature.^[9][10] NGF forms a cystine knot structure made up of beta strands twisted around each other and linked by 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

Rita Levi-Montalcini and Stanley Cohen discovered NGF in the 1950s while faculty members at 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 Nobel Prize in Physiology or Medicine.^[11][12][13]

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

Medical significance

NGF has the potential to help treat several diseases of the nervous system. It has shown this through numerous clinical trials. It has been shown to reduce neural degeneration.^[14] It has also been shown to promote peripheral nerve regeneration in rats.^[15]

There is strong evidence demonstrating more NGF is expressed in inflammatory ^[16] conditions. This may one day be used for the treatment of Multiple Sclerosis.^[17] Also, it could possibly promote myelin repair.^[18]

Also, NGF has been shown to play a role in number cardiovascular diseases, such as coronary atherosclerosis, obesity, type 2 diabetes, and metabolic syndrome.^[19] Reduced plasma levels of NGF and BDNF have been associated with acute coronary syndromes and metabolic syndromes.^[20][21] NGF could also be related to various psychiatric disorders, such as dementia, depression, schizophrenia, autism, Rett syndrome, anorexia nervosa, and bulimia nervosa.^[22] 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. ^[23]

NGF is known to have insulinotropic, angiogenic, and antioxidant properties. NGF suppresses food intake.

It has also been tied to Alzheimer's disease.^[24][25][26]

Cultural significance

In 2005, Enzo Emanuele and coworkers at University of Pavia found that nerve growth factor (NGF) has high levels when people first fall in 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.^[27][28][29]

Pietro Calissano has suggested that nerve growth factor may contribute to increased longevity and mental capacity.^[30] Centenarian Rita Levi-Montalcini has been taking 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.^[31]

Interactions

Nerve growth factor has been shown to interact with TrkA^[32][33][34] and Low affinity nerve growth factor receptor.^[32][33]

See also

• Protein targeting
• Nervous System
• VGF Nerve Growth Factor-inducible, a protein whose expression is induced by NGF
• neurotrophin
• growth factor
• brain-derived neurotrophic factor
• neurotrophin-3
• neurotrophin-4
• nerve growth factor receptor
• Hericium erinaceus an edible mushroom that has been shown to boost NGF
• Huperzine A an herb-derived alkaloid that seems to boost NGF

References

1. ^ Fiore M, Chaldakov GN, Aloe L (2009). "Nerve growth factor as a signaling molecule for nerve cells and also for the neuroendocrine-immune systems". Rev Neurosci 20 (2): 133–45. PMID 19774790. 
2. ^ Purves D, Augustine G, Fitzpatrick D, Hall W, LaMantia A, McNamara J, White L (2004). Neuroscience. Sunderland, Mass: Sinauer. pp. 72–173, 600–606. ISBN 0-87893-725-0. 
3. ^ MeSH Nerve+Growth+Factor
4. ^ MeSH Nerve+Growth+Factors
5. ^ Freeman RS, Burch RL, Crowder RJ, Lomb DJ, Schoell MC, Straub JA, Xie L (2004). NGF deprivation-induced gene expression: after ten years, where do we stand?. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 111–26. doi:10.1016/S0079-6123(03)46008-1. ISBN 9780444514721. PMID 14699960. 
6. ^ Madduri S, Papaloïzos M, Gander B (September 2009). "Synergistic effect of GDNF and NGF on axonal branching and elongation in vitro". Neurosci. Res. 65 (1): 88–97. doi:10.1016/j.neures.2009.06.003. PMID 19523996. 
7. ^ Levi-Montalcini R (2004). "The nerve growth factor and the neuroscience chess board". Prog. Brain Res. 146: 525–7. PMID 14699984. 
8. ^ Fahnestock M, Yu G, Coughlin MD (2004). ProNGF: a neurotrophic or an apoptotic molecule?. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 101–10. doi:10.1016/S0079-6123(03)46007-X. ISBN 9780444514721. PMID 14699959. 
9. ^ PDB 1bet; McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL (December 1991). "New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor". Nature 354 (6352): 411–4. doi:10.1038/354411a0. PMID 1956407. 
10. ^ "NGF - twenty years a-growing". Quips. Protein Data Bank Europe. http://www.ebi.ac.uk/pdbe-apps/quips?story=NGFstory. 
11. ^ The 1986 Nobel Prize in Physiology or Medicine for discoveries of growth factors
12. ^ Presentation Speech by Professor Kerstin Hall The Nobel Prize in Physiology or Medicine 1986
13. ^ Rita Levi-Montalcini – Nobel Lecture
14. ^ Tuszynski M., Blesch A. (2004). Nerve growth factor: from animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer’s disease. Progress in Brain Research, 146, 0079-6123
15. ^ Sun W, Sun C, Lin H, Zhao H, Wang J, Ma H, Chen B, Xiao Z, Dai J (September 2009). "The effect of collagen-binding NGF-beta on the promotion of sciatic nerve regeneration in a rat sciatic nerve crush injury model". Biomaterials 30 (27): 4649–56. doi:10.1016/j.biomaterials.2009.05.037. PMID 19573907. 
16. ^ Freund V, Frossard N (2004). Expression of nerve growth factor in the airways and its possible role in asthma. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 335–46. doi:10.1016/S0079-6123(03)46021-4. ISBN 9780444514721. PMID 14712791. 
17. ^ Villoslada P, Genain CP (2004). Role of nerve growth factor and other trophic factors in brain inflammation. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 403–14. doi:10.1016/S0079-6123(03)46025-1. ISBN 9780444514721. PMID 14699976. 
18. ^ Althaus HH (2004). Remyelination in multiple sclerosis: a new role for neurotrophins?. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 415–32. doi:10.1016/S0079-6123(03)46026-3. ISBN 9780444514721. PMID 14699977. 
19. ^ Chaldakov GN, Fiore M, Stankulov IS, Manni L, Hristova MG, Antonelli A, Ghenev PI, Aloe L (2004). Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease?. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 279–89. doi:10.1016/S0079-6123(03)46018-4. ISBN 9780444514721. PMID 14699970. 
20. ^ Chaldakov GN, Fiore M, Tonchev AB, Dimitrov D, Pancheva R, Rancic G, Aloe L (2007). "Homo obesus: a metabotrophin-deficient species. Pharmacology and nutrition insight". Curr. Pharm. Des. 13 (21): 2176–9. doi:10.2174/138161207781039616. PMID 17627549. 
21. ^ Manni L, Nikolova V, Vyagova D, Chaldakov GN, Aloe L (June 2005). "Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes". Int. J. Cardiol. 102 (1): 169–71. doi:10.1016/j.ijcard.2004.10.041. PMID 15939120. 
22. ^ Chaldakov G., Tonchev A., Aloe L. (2009). NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines. Relevance to neuropsychiatric and cardiometabolic.
23. ^ Kawamoto K, Matsuda H (2004). Nerve growth factor and wound healing. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 369–84. doi:10.1016/S0079-6123(03)46023-8. ISBN 9780444514721. PMID 14699974. 
24. ^ Counts S, Mufson E (2005). "The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease". J Neuropathol Exp Neurol 64 (4): 263–72. PMID 15835262. 
25. ^ Hempstead B (2006). "Dissecting the diverse actions of pro- and mature neurotrophins". Curr Alzheimer Res 3 (1): 19–24. doi:10.2174/156720506775697061. PMID 16472198. 
26. ^ Allen S, Dawbarn D (2006). "Clinical relevance of the neurotrophins and their receptors". Clin Sci (Lond) 110 (2): 175–91. doi:10.1042/CS20050161. PMID 16411894. 
27. ^ Emanuele E, Politi P, Bianchi M, Minoretti P, Bertona M, Geroldi D (2005). "Raised plasma nerve growth factor levels associated with early-stage romantic love". Psychoneuroendocrinology 31 (3): 288–94. doi:10.1016/j.psyneuen.2005.09.002. PMID 16289361.  link
28. ^ "NGF" gives passionate lovers just one year, Reuters, November 29, 2005.
29. ^ John Harris Is love just a chemical?, Guardian, November 29, 2005.
30. ^ Peter Popham (2009-04-25). "Is this the secret of eternal life?". London: The Independent. http://www.independent.co.uk/news/science/is-this-the-secret-of-eternal-life-1674005.html. 
31. ^ Popham, Peter (April 25, 2009). "Is this the secret of eternal life?". The Independent (London). http://www.independent.co.uk/news/science/is-this-the-secret-of-eternal-life-1674005.html. 
32. ^ ^{a b} Nykjaer, Anders; Lee Ramee, Teng Kenneth K, Jansen Pernille, Madsen Peder, Nielsen Morten S, Jacobsen Christian, Kliemannel Marco, Schwarz Elisabeth, Willnow Thomas E, Hempstead Barbara L, Petersen Claus M (Feb. 2004). "Sortilin is essential for proNGF-induced neuronal cell death". Nature (England) 427 (6977): 843–8. doi:10.1038/nature02319. PMID 14985763. 
33. ^ ^{a b} Lee, R; Kermani P, Teng K K, Hempstead B L (Nov. 2001). "Regulation of cell survival by secreted proneurotrophins". Science (United States) 294 (5548): 1945–8. doi:10.1126/science.1065057. ISSN 0036-8075. PMID 11729324. 
34. ^ Wiesmann, C; Ultsch M H, Bass S H, de Vos A M (Sep. 1999). "Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor". Nature (ENGLAND) 401 (6749): 184–8. doi:10.1038/43705. ISSN 0028-0836. PMID 10490030. 

External links

• MeSH Nerve+Growth+Factor
• , NGF for corneal therapeutic purposes,