Neurturin

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neurturin
Identifiers
Symbol NRTN
Alt. symbols NTN
Entrez 4902
HUGO 8007
OMIM 602018
RefSeq NM_004558
UniProt Q99748
Other data
Locus Chr. 19 p13.3

Terminology

Neurturin (NRTN) belongs to the glial cell-line derived neurotrophic factor (GDNF) family of ligands called neurotrophins, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the TGF-beta (transforming growth factor) subfamily along with it’s homologs persephin, artemin, and GDNF.[1] It is also considered a trophic factor and critical in the development and growth of neurons in the brain.[2] Neurotrophic factors like neurturin have been tested in several clinical trial setting for the potential treatment of neurodegenerative diseases, specifically Parkinsons Disease.[3]

Function

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.[4] 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.[7]

Mechanism of Activation

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.[8]

Interactions

Neurturin has been shown to upregulate B1 (bradykinin) receptors in neurons of mice, indicating a possible influence on pain and inflammation pathways.[9] In addition knockout mice have shown that in the absence of neurturin an increased acetylcholine response is observed.[10] The exact role and function of neurturin in multiple signaling pathways is widely unknown.

Role in Disease

The most studied is neurturin’s role in neurodegenerative disease like Parkinsons disease and Huntingtons, where several rat studies have implicated neurturin’s role in rescuing neurons.[11] 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 along 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.[12] A more recent study showed NRTN variants present in individuals with Hirschsprung disease.[13] 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.[14] Lastly, a study also associated neurturin deficiency in mice with keratoconjunctivitis and dry eye.[15]

Potential for Therapeutics

Clinical Trial

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 it’s 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.[16] The hope was to reverse damaged and diseased tissue in Parkinsons 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. Neurturin’s therapeutic potential is unknown and future studies aim to improve delivery of the drug.[17]

References[edit]

  1. ^ Widenfalk, J., Nosrat, C., Tomac, A., Westphal, H., Hoffer, B., & Olson, L. (1997). Neurturin and glial cell line-derived neurotrophic factor receptor-β (GDNFR-β), novel proteins related to GDNF and GDNFR-α 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), 8506-8519.http://www.jneurosci.org/content/17/21/8506.full.pdf
  2. ^ Golden, J. P., DeMaro, J. A., Osborne, P. A., Milbrandt, J., & Johnson, E. M. (1999). Expression of neurturin, GDNF, and GDNF family-receptor mRNA in the developing and mature mouse. Experimental neurology, 158(2), 504-528.http://www.ncbi.nlm.nih.gov/pubmed/10415156
  3. ^ Evans, J. R., & Barker, R. A. (2008). Neurotrophic factors as a therapeutic target for Parkinson's disease.http://www.ncbi.nlm.nih.gov/pubmed/18348680
  4. ^ Horger, B. A., Nishimura, M. C., Armanini, M. P., Wang, L. C., Poulsen, K. T., Rosenblad, C., ... & Phillips, H. S. (1998). Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. The Journal of neuroscience, 18(13), 4929-4937.http://www.jneurosci.org/content/18/13/4929.full.pdf
  5. ^ Horger, B. A., Nishimura, M. C., Armanini, M. P., Wang, L. C., Poulsen, K. T., Rosenblad, C., ... & Phillips, H. S. (1998). Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. The Journal of neuroscience, 18(13), 4929-4937.http://www.jneurosci.org/content/18/13/4929.full.pdf
  6. ^ Heuckeroth, R. O., Enomoto, H., Grider, J. R., Golden, J. P., Hanke, J. A., Jackman, A., ... & Milbrandt, J. (1999). Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron, 22(2), 253-263.http://www.ncbi.nlm.nih.gov/pubmed/10069332?dopt=Abstract
  7. ^ Heuckeroth, R. O., Enomoto, H., Grider, J. R., Golden, J. P., Hanke, J. A., Jackman, A., ... & Milbrandt, J. (1999). Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron, 22(2), 253-263.http://www.ncbi.nlm.nih.gov/pubmed/10069332?dopt=Abstract
  8. ^ Creedon, D. J., Tansey, M. G., Baloh, R. H., Osborne, P. A., Lampe, P. A., Fahrner, T. J., ... & Johnson, E. M. (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, 94(13), 7018-7023.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC21277/
  9. ^ Vellani, V., Zachrisson, O., & McNaughton, P. A. (2004). Functional bradykinin B1 receptors are expressed in nociceptive neurones and are upregulated by the neurotrophin GDNF. The Journal of physiology, 560(2), 391-401.http://www.ncbi.nlm.nih.gov/pubmed/15319421?dopt=Abstract
  10. ^ Nangle, M. R., & Keast, J. R. (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), 423-433.http://www.ncbi.nlm.nih.gov/pubmed/16682963?dopt=Abstract
  11. ^ Horger, B. A., Nishimura, M. C., Armanini, M. P., Wang, L. C., Poulsen, K. T., Rosenblad, C., ... & Phillips, H. S. (1998). Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. The Journal of neuroscience, 18(13), 4929-4937.http://www.jneurosci.org/content/18/13/4929.full
  12. ^ Doray, B., Salomon, R., Amiel, J., Pelet, A., Touraine, R., Billaud, M., ... & Lyonnet, S. (1998). Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Human molecular genetics, 7(9), 1449-1452.http://www.ncbi.nlm.nih.gov/pubmed/9700200
  13. ^ Ruiz-Ferrer M, Torroglosa A, Luzón-Toro B, Fernández RM, Antiñolo G, Mulligan LM, Borrego S. 2011. Novel mutations at RET ligand genes preventing receptor activation are associated to Hirschsprung’s disease. Journal of Molecular Medicine 89: 471–480.
  14. ^ Camassei, F. D., Boldrini, R., Jenkner, A., Inserra, A., Donfrancesco, A., Ravà, L., & Dominici, C. (2003). Expression of glial cell line-derived neurotrophic factor and neurturin in mature kidney, nephrogenic rests, and nephroblastoma: possible role as differentiating factors. Pediatric and Developmental Pathology, 6(6), 511-519.http://www.ncbi.nlm.nih.gov/pubmed/15018450
  15. ^ Song, X. J., Li, D. Q., Farley, W., Luo, L. H., Heuckeroth, R. O., Milbrandt, J., & Pflugfelder, S. C. (2003). Neurturin-deficient mice develop dry eye and keratoconjunctivitis sicca. Investigative ophthalmology & visual science, 44(10), 4223-4229.http://www.ncbi.nlm.nih.gov/pubmed/14507865
  16. ^ Gasmi, M., Brandon, E. P., Herzog, C. D., Wilson, A., Bishop, K. M., Hofer, E. K., ... & Bartus, R. T. (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.
  17. ^ https://www.michaeljfox.org/foundation/news-detail.php?news-in-context-second-phase-trial-of-cere-120-yields-disappointing-results

External links[edit]