Neurturin
| 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 |
Neurturin (NRTN) is a protein. 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 TGF-beta (transforming growth factor) subfamily along with its homologs persephin, artemin, and GDNF. It is also considered a trophic factor and critical in the development and growth of neurons in the brain. Neurotrophic factors like neurturin have been tested in several clinical trial setting for the potential treatment of neurodegenerative diseases, specifically Parkinsons Disease.
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. In vivo the direct administration of neurturin into substantia nigra of mice models also shows mature DA neuron protection. 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. 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.
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.
Neurturin has been shown to upregulate B1 (bradykinin) receptors in neurons of mice, indicating a possible influence on pain and inflammation pathways. In addition knockout mice have shown that in the absence of neurturin an increased acetylcholine response is observed. The exact role and function of neurturin in multiple signaling pathways is widely unknown.
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. 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. A more recent study showed NRTN variants present in individuals with Hirschsprung disease. 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. Lastly, a study also associated neurturin deficiency in mice with keratoconjunctivitis and dry eye.
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