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Neurturin

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Neurturin
Identifiers
SymbolNRTN
Alt. symbolsNTN
NCBI gene4902
HGNC8007
OMIM602018
RefSeqNM_004558
UniProtQ99748
Other data
LocusChr. 19 p13.3
Search for
StructuresSwiss-model
DomainsInterPro

Neurturin (NRTN) is a protein that is encoded in humans by the NRTN gene. Neurturin belongs to the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the transforming growth factor beta (TGF-beta) subfamily along with its homologs persephin, artemin, and GDNF.[1] It shares a 42% similarity in amino acid sequence with mature GDNF.[2] It is also considered a trophic factor and critical in the development and growth of neurons in the brain.[3] Neurotrophic factors like neurturin have been tested in several clinical trial settings for the potential treatment of neurodegenerative diseases, specifically Parkinson's disease.[4]

Function

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Neurturin is encoded for by the NRTN gene located on chromosome 19 in humans and has been shown to promote potent effects on survival and function of developing and mature midbrain dopaminergic neurons (DA) in vitro.[5] In vivo the direct administration of neurturin into substantia nigra of mice models also shows mature DA neuron protection.[5] In addition, neurturin has also been shown to support the survival of several other neurons including sympathetic and sensory neurons of the dorsal root ganglia.[6] Knockout mice have shown that neurturin does not appear essential for survival. However, evidence shows retarded growth of enteric, sensory and parasympathetic neurons in mice upon the removal of neurturin receptors.[6]

Mechanism of activation

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Neurturin signaling is mediated by the activation of a multi-component receptor system including the ret tyrosine kinase (RET), a cell-surface bound GDNF family receptor-α (GFRα) protein, and a glycosyl phosphatidylinositol (GPI)-linked protein. Neurturin preferentially binds to the GFRα2 co-receptor. Upon assembly of the complex, specific tyrosine residues are phosphorylated within two molecules of RET that are brought together to initiate signal transduction and the MAP kinase signaling pathway.[7]

Interactions

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Neurturin has been shown to upregulate B1 (bradykinin) receptors in neurons of mice, indicating a possible influence on pain and inflammation pathways.[8] In addition knockout mice have shown that in the absence of neurturin an increased acetylcholine response is observed.[9] The exact role and function of neurturin in multiple signaling pathways is widely unknown.

Role in disease

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The most studied is neurturin’s role in neurodegenerative disease like Parkinson's disease and Huntington's, where several rat studies have implicated neurturin’s role in rescuing neurons.[5] However, these results have never been observed in humans. Hirschsprung disease, a autosomal dominant genetic disorder, is characterized by complete absence of neuronal ganglion cells from the intestinal tract. Previous studies indicate a role of NRTN gene mutations in the disease. One study showed evidence that a mutation in the NRTN gene was not enough alone to cause onset of the disease, however when coupled with a mutation in the RET gene, disease was present in family members as well as the individual.[10] A more recent study showed NRTN variants present in individuals with Hirschsprung disease.[11] However, RET associated mutations were not found and in one variant, RET phosphorylation levels were reduced, which has the potential to have downstream effects on the proliferation and differentiation of neuronal crests. Also, high levels of expression of neurturin were found to be associated with nephroblastoma indicating the possible that the growth factor could be influencing differentiation.[12] Lastly, a study also associated neurturin deficiency in mice with keratoconjunctivitis and dry eye.[13]

Therapeutic potential

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Evidence showing neurturin’s role in neuron survival and management has made it a popular candidate for the potential treatment or reversal of neurodegeneration. In addition, mice models have shown the dying neurons exposed to trophic factors can be rescued. Neurturin is an example of a trophic factor that is difficult to utilize clinically because of its inability to cross the blood-brain barrier of the CNS (central nervous system). Ceregene sponsored a double-blind phase II clinical trial of CERE-120, a viral vector mediated gene transfer drug that allows for the continuous delivery of neurturin to the nigrostratial system.[14] The hope was to reverse damaged and diseased tissue in Parkinson's patients and overall slow the progression of the disease. However, results were inconclusive and showed that while the drug appears to be relatively safe, there was no statistically significant data supporting the improvement of motor function or neuronal health.[citation needed] Neurturin’s therapeutic potential is unknown and future studies aim to improve delivery of the drug.[15]

References

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  1. ^ Widenfalk J, Nosrat C, Tomac A, Westphal H, Hoffer B, Olson L (Nov 1997). "Neurturin and glial cell line-derived neurotrophic factor receptor-beta (GDNFR-beta), novel proteins related to GDNF and GDNFR-alpha with specific cellular patterns of expression suggesting roles in the developing and adult nervous system and in peripheral organs". The Journal of Neuroscience. 17 (21): 8506–19. doi:10.1523/JNEUROSCI.17-21-08506.1997. PMC 6573771. PMID 9334423.
  2. ^ Kotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, Creedon DJ, Johnson Jr EM, Milbrandt J (1996). "Neurturin, a relative of glial-cell-line-derived neurotrophic factor". Nature. 384 (6608): 467–70. Bibcode:1996Natur.384..467K. doi:10.1038/384467a0. PMID 8945474. S2CID 4238843.
  3. ^ Golden JP, DeMaro JA, Osborne PA, Milbrandt J, Johnson EM (Aug 1999). "Expression of neurturin, GDNF, and GDNF family-receptor mRNA in the developing and mature mouse". Experimental Neurology. 158 (2): 504–28. doi:10.1006/exnr.1999.7127. PMID 10415156. S2CID 5755681.
  4. ^ Evans JR, Barker RA (Apr 2008). "Neurotrophic factors as a therapeutic target for Parkinson's disease". Expert Opinion on Therapeutic Targets. 12 (4): 437–47. doi:10.1517/14728222.12.4.437. PMID 18348680. S2CID 71281998.
  5. ^ a b c Horger BA, Nishimura MC, Armanini MP, Wang LC, Poulsen KT, Rosenblad C, Kirik D, Moffat B, Simmons L, Johnson E, Milbrandt J, Rosenthal A, Bjorklund A, Vandlen RA, Hynes MA, Phillips HS (Jul 1998). "Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons". The Journal of Neuroscience. 18 (13): 4929–37. doi:10.1523/JNEUROSCI.18-13-04929.1998. PMC 6792569. PMID 9634558.
  6. ^ a b Heuckeroth RO, Enomoto H, Grider JR, Golden JP, Hanke JA, Jackman A, Molliver DC, Bardgett ME, Snider WD, Johnson EM, Milbrandt J (Feb 1999). "Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons". Neuron. 22 (2): 253–63. doi:10.1016/S0896-6273(00)81087-9. PMID 10069332.
  7. ^ Creedon DJ, Tansey MG, Baloh RH, Osborne PA, Lampe PA, Fahrner TJ, Heuckeroth RO, Milbrandt J, Johnson EM (Jun 1997). "Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons". Proceedings of the National Academy of Sciences of the United States of America. 94 (13): 7018–23. Bibcode:1997PNAS...94.7018C. doi:10.1073/pnas.94.13.7018. JSTOR 42271. PMC 21277. PMID 9192684.
  8. ^ Vellani V, Zachrisson O, McNaughton PA (Oct 2004). "Functional bradykinin B1 receptors are expressed in nociceptive neurones and are upregulated by the neurotrophin GDNF". The Journal of Physiology. 560 (Pt 2): 391–401. doi:10.1113/jphysiol.2004.067462. PMC 1665249. PMID 15319421.
  9. ^ Nangle MR, Keast JR (Jun 2006). "Loss of nitrergic neurotransmission to mouse corpus cavernosum in the absence of neurturin is accompanied by increased response to acetylcholine". British Journal of Pharmacology. 148 (4): 423–33. doi:10.1038/sj.bjp.0706760. PMC 1751790. PMID 16682963.
  10. ^ Doray B, Salomon R, Amiel J, Pelet A, Touraine R, Billaud M, Attié T, Bachy B, Munnich A, Lyonnet S (Sep 1998). "Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease". Human Molecular Genetics. 7 (9): 1449–52. doi:10.1093/hmg/7.9.1449 (inactive 1 November 2024). PMID 9700200.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  11. ^ Ruiz-Ferrer M, Torroglosa A, Luzón-Toro B, Fernández RM, Antiñolo G, Mulligan LM, Borrego S (May 2011). "Novel mutations at RET ligand genes preventing receptor activation are associated to Hirschsprung's disease". Journal of Molecular Medicine. 89 (5): 471–80. doi:10.1007/s00109-010-0714-2. hdl:10261/71052. PMID 21206993. S2CID 22785920.
  12. ^ Chao SE, Scandalios JG (1972). "Developmentally dependent expression of tissue specific amylases in maize". Molecular & General Genetics. 115 (1): 1–9. doi:10.1007/bf00272211. PMID 5018450. S2CID 25195964.
  13. ^ Song XJ, Li DQ, Farley W, Luo LH, Heuckeroth RO, Milbrandt J, Pflugfelder SC (Oct 2003). "Neurturin-deficient mice develop dry eye and keratoconjunctivitis sicca". Investigative Ophthalmology & Visual Science. 44 (10): 4223–9. doi:10.1167/iovs.02-1319. PMID 14507865.
  14. ^ Gasmi M, Brandon EP, Herzog CD, Wilson A, Bishop KM, Hofer EK, Cunningham JJ, Printz MA, Kordower JH, Bartus RT (Jul 2007). "AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: long-term efficacy and tolerability of CERE-120 for Parkinson's disease". Neurobiology of Disease. 27 (1): 67–76. doi:10.1016/j.nbd.2007.04.003. PMID 17532642. S2CID 33685407.
  15. ^ Herpich N (April 19, 2013). "News in Context: Second Phase 2 Trial of CERE-120 Yields Disappointing Results". Foxfeed Blog. Michael J. Fox Foundation.
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