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From Proteopedia

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Introduction

Ciliary Neurotrophic Factor (CNTF) is a nerve growth factor belonging to the Interleukin-6 (IL-6) family of neuropoietic cytokines. Other members of this family include leukemia inhibitory factor (LIF), IL-6, IL-11 and oncostatin M (Wang 2012).

CNTF exerts its biological function by binding into a tripartite receptor complex consisting of a specific CNTF receptor subunit α (CNTFRα) linked to the cell membrane with a glycosyl-phosphatidylinositol linkage, and two signal-transducing transmembrane subunits LIF receptor beta (LIFRβ) and gp130. Binding of a hCNTF dimer to CNTFRα is the absolute first requirement to initiate a signal transduction cascade, which ultimately results in the enhanced transcription of genes encoding e.g. acute phase plasma proteins, and suppressors of cytokine signaling. CNTFRα has been observed to exist also as a soluble receptor (sCNTFRα) (Panayotatos et al. 1994), attributed to a phospholipase C-mediated cleavage (Davis et al. 1993). This has been postulated to offer a partial explanation as to why cells expressing LIFRβ and gp130 but not CNTFRα, are nonetheless responsive to CNTF.

CNTF's known biological functions involve affecting the growth, differentiation, survival and repair of various types of neurons and glial cells in both the central and peripheral nervous systems (Sleeman et al. 2000, Cognet et al. 2004); evidence also suggests CNTF to be expressed in other tissues, such as adipocytes and hepatocytes among others (). As the transcription of CNTF mRNA and CNTF distribution have been noticed to be altered upon neural injury, it has been suggested, that CNTF is not an absolute requirement for neural development, but in fact mainly acts in response to neural injuries and stresses . Furthermore, mice homozygous for an inactived CNTF gene have been observed to develop normally, and to display losses in motor neurons only later during adulthood. Although humans homozygous for an inactivated CNTF gene caused by a mutation have not been observed to suffer from major neurological abnormalities (Wang 2012), this has been linked with early onset of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) (Cognet et al. 2004). However, mice that have a CNTFRα knock-out die already during the perinatal stage and exhibit severe motor neuron deficits (Sleeman et al. 2000), suggesting that CNTFRα might have a second ligand.

Fig. 1 X-ray structure of a truncated form of hCNTF (2-187)

Structure

Overview

CNTF is a roughly 22.7 kDa protein consisting of a single polypeptide chain of 200 amino acid residues. Like with many other cytokines, the tertiary structure of CNTF consists of four anti-parallel α-helices (A-D), where helices A-B and C-D are connected by two cross-over loops and helices B-C by one short loop.

(Kallen et al. 1999) CNTF LIFR binding epitope

Disease

While not directly linked to disease, CNTF has been shown to inhibit the secretion of VEGF in the human retina, alleviating the symptoms of some ocular diseases (Li 2011). It has been proposed that treatment with CNTF could counteract vision loss caused by age-related loss of vision, retinitis pigmentosa and retinitis pigmentosa linked to Usher syndrome. In these cases the alleviating effect is produced by CNTF inducing regeneration of outer segments of cone cells in the retina (Li 2010). Using capsulated cells transfected with the human CNTF gene has been studied as a delivery method (Sieving 2006, Talcott 2011).

A frameshift mutation in exon 2 of the CNTF gene affecting some 2-3 % of the population (Takahashi 1994) causes earlier onset of the disease and quicker declination of motor neuron function in MS patients (Giess 2002). MS patients with functional CNTF show 1,7-fold increase of CNTF mRNA expression in the cortex, suggesting CNTF secretion as an innate response to progressing neuronal damage (Duetta 2007).

References

Cognet I, Guilhot F, Chevalier S, Guay-Giroux A, Bert A, Elson GCA, Gascan H and Gauchat J-F: Expression of biologically active mouse ciliary neurotrophic factor (CNTF) and soluble CNTFRα in Eschericia coli and characterization of their functional specificities. Eur Cytokine Netw 15: 255-262 (2004).

Li Y, Tao W, Luo L, Huang D, Kauper K, Stabila P, LaVail MM, Laties AM and Wen R: CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One 5: 1-7 (2010).

Li Y, Wen R, Banzon T, Maminishkis A and Miller SS: CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium. PLoS One 6: 1-7 (2011).

McDonald NQ, Panayotatos N and Hendrickson WA: Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. EMBO J 14: 2689-2699 (1995).

Richardson PM: Ciliary neurotrophic factor: A review. Pharmac Ther 63: 187-198 (1994).

Sieving PA, Caruse RC, Tao W, Coleman HR, Thompson DJS, Fullmer KR and Bush RA: Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implants. PNAS 103: 3896-3901 (2006).

Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD and Wiegand SJ: The ciliary neurotrophic factor and its receptor, CNTFRα. Pharm Acta Helv 74: 265-272 (2000).

Wen R, Song Y, Kjellstrom S, Tanikawa A, Liu Y, Li Y, Zhao L, Bush RA, Laties AM and Sieving PA: Regulation of rod phototransduction machinery by ciliary neurotrophic factor. J Neurosci 26: 13523-13530 (2006).

Wen R, Tao W, Li Y and Sieving PA: CNTF and retina. Prog Retin Eye Res 31: 136-151 (2012).