Glial cell line-derived neurotrophic factor
Encyclopedia : G : GL : GLI : Glial cell line-derived neurotrophic factor
GDNF
Glial cell line-Derived Neurotrophic Factor (GDNF) is a small protein that potently promotes the survival of many types of neurons. The most prominent feature of GDNF is its ability to support the survival of dopaminergic and motorneurons. These neuronal populations die in the course of Parkinson’s disease and amyotrophic lateral sclerosis (ALS) respectively. GDNF also regulates kidney development and spermatogenesis.
GDNF is a founding member of the GDNF family of ligands (GFL), which consists of four neurotrophic factors: GDNF, neurturin (NRTN), artemin (ARTN) and persephin (PSPN) [link].
The receptor complex for GFL consists of the signalling module, a receptor tyrosine kinase RET, and a cell surface-bound co-receptor, the GDNF family receptor α (GFRα). Upon ligand activation, this complex promotes cell survival, neurite outgrowth, cell differentiation, cell migration and other processes. In particular, the activation of RET by GDNF promotes the survival of dopaminergic neurons. Therefore, GDNF is an important therapeutical target for the Parkinson’s disease. GDNF has shown promising results in one Parkinson’s disease clinical trial [link] and in a number of animal trials. However, a different study failed to show strong clinical benefits of GDNF [link]. GDNF is a potent survival factor for central motoneurons and may have clinical importance for the treatment of ALS [link]. Moreover, recent results highlight the importance of GDNF as a new target for drug addiction [link] and alcoholism treatment [link].
NRTN can also be used for Parkinson’s disease therapy and for epilepsy treatment [link]. NRTN promotes survival of basal forebrain cholinergic neurons [link] and spinal motor neurons [link]. 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 [link]. PSPN promotes the survival of mouse embryonic basal forebrain cholinergic neurons in vitro [link]. Hence, PSPN may be used for the treatment of Alzheimer’s disease. PSPN may also have clinical applications in the treatment of the stroke [link].
Given a huge spectrum of possible therapeutical 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.
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