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.

Structure
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. 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.

Signalling 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 sulphate glycosaminoglycans are also required to be present at the cell surface in order for RET mediated GDNF signalling to occur.

Clinical significance
GFLs are an important therapeutical target for several conditions:


 * GDNF has shown promising results in two Parkinson's disease clinical trial 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. GNDF is a potent survival factor for central motoneurons and may have clinical importance for the treatment of ALS. Moreover, recent results highlight the importance of GDNF as a new target for drug addiction and alcoholism treatment.


 * NRTN can also be used for Parkinson’s disease therapy and for epilepsy treatment. NRTN promotes survival of basal forebrain cholinergic neurons and spinal motor neurons. 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.


 * 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.

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.