GDNF family of ligands

The GDNF family of ligands (GFL) consists of four neurotrophic factors: glial cell line-derived neurotrophic factor (GDNF) neurturin (NRTN), artemin (ARTN) and persephin (PSPN). GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration. In particular signalling by GDNF promotes the survival of dopaminergic neurons.cite journal |author=Airaksinen M, Saarma M |title=The GDNF family: signalling, biological functions and therapeutic value |journal=Nat Rev Neurosci |volume=3 |issue=5 |pages=383–94 |year=2002 |pmid=11988777 |doi=10.1038/nrn812]

tructure

Members of the GFL family only share around 40% amino acid sequence identity, however all GFLs are distantly related to the transforming growth factor-β (TGF-β) superfamily of proteins. Both GFLs and members of the TGF-β superfamily share a similar conformation and belong to the cystine knot protein family.cite journal |author=Ibanez CF |title=Emerging themes in structural biology of neurotrophic factors |journal=Trends Neurosci. |volume=21 |issue=10 |pages=438–444 |year=1998 |pmid=9786342 |doi=10.1016/S0166-2236(98)01266-1] GFLs do not signal through transforming growth factor beta receptors and as such are not strictly members of the transforming growth factor beta superfamily.GFLs function as homodimers and are initially synthesised as an inactive precursor molecule, preproGFL. The "pre" signal sequence is removed upon the proteins secretion and the "pro" sequence removed sometime later to produce active GFL, possibly at the cell surface of target cells.cite journal | author = Arighi E, Borrello MG, Sariola H. | title = RET tyrosine kinase signaling in development and cancer | journal = Cytokine Growth Factor Rev. | year=2005 | volume=16 | issue=4-5 | pages=441–467 | pmid = 15982921 | doi = 10.1016/j.cytogfr.2005.05.010]

ignalling complex formation

At the cell surface of target cells a signalling complex forms, composed of a particular GFL dimer, a receptor tyrosine kinase molecule RET, and a cell surface-bound co-receptor which is a member of the GFRα protein family. The primary ligands for the co-receptors GFRα1, GFRα2, GFRα3 and GFRα4 are GDNF, NRTN, ARTN and PSPN respectively. Upon initial GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each RET molecule. Phosphorylation of these tyrosines then initiates intracellular signal transduction processes.

It has been shown that in the case of GDNF, heparan sulfate glycosaminoglycans are also required to be present at the cell surface in order for RET mediated GDNF signalling to occur.cite journal |author=Barnett MW, Fisher CE. "et al" | title=Signalling by glial cell line-derived neurotrophic factor (GDNF) requires heparan sulfate glycosaminoglycan | journal=J. Cell. Sci. | volume=115 |issue=23 | pages=4495–4503 | year=2002 | pmid=12414995 | doi=10.1242/jcs.00114]

Clinical significance

GFLs are an important therapeutical target for several conditions:

* GDNF has shown promising results in two Parkinson's disease clinical trial [cite journal |author=Gill S, Patel N, Hotton G, O'Sullivan K, McCarter R, Bunnage M, Brooks D, Svendsen C, Heywood P |title=Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease |journal=Nat Med |volume=9 |issue=5 |pages=589–95 |year=2003 |pmid=12669033 |doi=10.1038/nm850] [cite journal |author=Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B |title=Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor |journal=J. Neurosurg. |volume=102 |issue=2 |pages=216–22 |year=2005 |pmid=15739547] and in a number of animal trials. Although a different study later reported this as a 'placebo effect', work on perfecting the delivery of GDNF to the putamen is continuing. GDNF is a potent survival factor for central motoneurons and may have clinical importance for the treatment of ALS. [cite journal |author=Henderson C, Phillips H, Pollock R, Davies A, Lemeulle C, Armanini M, Simmons L, Moffet B, Vandlen R, Simpson LC [corrected to Simmons L |title=GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle |journal=Science |volume=266 |issue=5187 |pages=1062–4 |year=1994 |pmid=7973664 |doi=10.1126/science.7973664] Moreover, recent results highlight the importance of GDNF as a new target for drug addiction [cite journal |author=Airavaara M, Planken A, Gäddnäs H, Piepponen T, Saarma M, Ahtee L |title=Increased extracellular dopamine concentrations and FosB/DeltaFosB expression in striatal brain areas of heterozygous GDNF knockout mice |journal=Eur J Neurosci |volume=20 |issue=9 |pages=2336–44 |year=2004 |pmid=15525275 |doi=10.1111/j.1460-9568.2004.03700.x] and alcoholism treatment. [cite journal |author=He D, McGough N, Ravindranathan A, Jeanblanc J, Logrip M, Phamluong K, Janak P, Ron D |title=Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption |journal=J Neurosci |volume=25 |issue=3 |pages=619–28 |year=2005 |pmid=15659598 |doi=10.1523/JNEUROSCI.3959-04.2005]

* NRTN can also be used for Parkinson’s disease therapy and for epilepsy treatment. [cite journal |author=Horger B, Nishimura M, Armanini M, Wang L, Poulsen K, Rosenblad C, Kirik D, Moffat B, Simmons L, Johnson E, Milbrandt J, Rosenthal A, Bjorklund A, Vandlen R, Hynes M, Phillips H |title=Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons |journal=J Neurosci |volume=18 |issue=13 |pages=4929–37 |year=1998 |pmid=9634558] NRTN promotes survival of basal forebrain cholinergic neurons cite journal |author=Golden J, Milbrandt J, Johnson E |title=Neurturin and persephin promote the survival of embryonic basal forebrain cholinergic neurons in vitro |journal=Exp Neurol |volume=184 |issue=1 |pages=447–55 |year=2003 |pmid=14637114 |doi=10.1016/j.expneurol.2003.07.999] and spinal motor neurons. [cite journal |author=Garcès A, Livet J, Grillet N, Henderson C, Delapeyrière O |title=Responsiveness to neurturin of subpopulations of embryonic rat spinal motoneuron does not correlate with expression of GFR alpha 1 or GFR alpha 2 |journal=Dev Dyn |volume=220 |issue=3 |pages=189–97 |year=2001 |pmid=11241828 |doi=10.1002/1097-0177(20010301)220:3<189::AID-DVDY1106>3.0.CO;2-I |doilabel=10.1002/1097-0177(20010301)220:3189::AID-DVDY11063.0.CO;2-I] Therefore, NRTN has a potential in the treatment of Alzheimer’s disease and ALS.

* ARTN also has a therapeutical perspective, for it is considered for chronical pain treatment. [cite journal |author=Gardell L, Wang R, Ehrenfels C, Ossipov M, Rossomando A, Miller S, Buckley C, Cai A, Tse A, Foley S, Gong B, Walus L, Carmillo P, Worley D, Huang C, Engber T, Pepinsky B, Cate R, Vanderah T, Lai J, Sah D, Porreca F |title=Multiple actions of systemic artemin in experimental neuropathy |journal=Nat Med |volume=9 |issue=11 |pages=1383–9 |year=2003 |pmid=14528299 |doi=10.1038/nm944]

* PSPN promotes the survival of mouse embryonic basal forebrain cholinergic neurons "in vitro". ] Hence, PSPN may be used for the treatment of Alzheimer’s disease. PSPN may also have clinical applications in the treatment of the stroke. [cite journal |author=Tomac A, Agulnick A, Haughey N, Chang C, Zhang Y, Bäckman C, Morales M, Mattson M, Wang Y, Westphal H, Hoffer B |title=Effects of cerebral ischemia in mice deficient in Persephin |journal=Proc Natl Acad Sci U S A |volume=99 |issue=14 |pages=9521–6 |year=2002 |pmid=12093930 |doi=10.1073/pnas.152535899]

Given a huge spectrum of possible therapeutic applications, the modulation of GFRα/RET receptor complex activity is of great interest. However, natural GDNF ligands are of a limited clinical use. As positively charged polypeptides GFLs are unable to penetrate the blood-brain barrier and they have very small volume of distribution in the tissues. Therefore, the creation of small-molecule agonists is highly beneficial for the development of effective therapies against devastating neurological diseases [cite journal |author=Bespalov M.M. and Saarma M. |title=GDNF family receptor complexes are emerging drug targets |journal=Trends Pharmacol Sci. |volume=28 |issue=2 |pages=68–74 |year=2007 |pmid=17218019 |doi=10.1016/j.tips.2006.12.005] .

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