GDNF family of ligands

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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).[1]

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.

[edit] Clinical significance

Because of these functions, GDNF is an important therapeutical target for several conditions:

  • GDNF has shown promising results in one Parkinson's disease clinical trial [2] 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. [3] Moreover, recent results highlight the importance of GDNF as a new target for drug addiction [4] and alcoholism treatment. [5]
  • NRTN can also be used for Parkinson’s disease therapy and for epilepsy treatment. [6] NRTN promotes survival of basal forebrain cholinergic neurons [7] and spinal motor neurons.[8] 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. [9]
  • PSPN promotes the survival of mouse embryonic basal forebrain cholinergic neurons in vitro.[7] Hence, PSPN may be used for the treatment of Alzheimer’s disease. PSPN may also have clinical applications in the treatment of the stroke.[10]

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.

[edit] References

  1. ^ Airaksinen M, Saarma M (2002). "The GDNF family: signalling, biological functions and therapeutic value". Nat Rev Neurosci 3 (5): 383-94. PMID 11988777. 
  2. ^ Gill S, Patel N, Hotton G, O'Sullivan K, McCarter R, Bunnage M, Brooks D, Svendsen C, Heywood P (2003). "Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease". Nat Med 9 (5): 589-95. PMID 12669033. 
  3. ^ Henderson C, Phillips H, Pollock R, Davies A, Lemeulle C, Armanini M, Simmons L, Moffet B, Vandlen R, Simpson LC [corrected to Simmons L (1994). "GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle". Science 266 (5187): 1062-4. PMID 7973664. 
  4. ^ Airavaara M, Planken A, Gäddnäs H, Piepponen T, Saarma M, Ahtee L (2004). "Increased extracellular dopamine concentrations and FosB/DeltaFosB expression in striatal brain areas of heterozygous GDNF knockout mice". Eur J Neurosci 20 (9): 2336-44. PMID 15525275. 
  5. ^ He D, McGough N, Ravindranathan A, Jeanblanc J, Logrip M, Phamluong K, Janak P, Ron D (2005). "Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption". J Neurosci 25 (3): 619-28. PMID 15659598. 
  6. ^ 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 (1998). "Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons". J Neurosci 18 (13): 4929-37. PMID 9634558. 
  7. ^ a b Golden J, Milbrandt J, Johnson E (2003). "Neurturin and persephin promote the survival of embryonic basal forebrain cholinergic neurons in vitro". Exp Neurol 184 (1): 447-55. PMID 14637114. 
  8. ^ Garcès A, Livet J, Grillet N, Henderson C, Delapeyrière O (2001). "Responsiveness to neurturin of subpopulations of embryonic rat spinal motoneuron does not correlate with expression of GFR alpha 1 or GFR alpha 2". Dev Dyn 220 (3): 189-97. PMID 11241828. 
  9. ^ 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 (2003). "Multiple actions of systemic artemin in experimental neuropathy". Nat Med 9 (11): 1383-9. PMID 14528299. 
  10. ^ Tomac A, Agulnick A, Haughey N, Chang C, Zhang Y, Bäckman C, Morales M, Mattson M, Wang Y, Westphal H, Hoffer B (2002). "Effects of cerebral ischemia in mice deficient in Persephin". Proc Natl Acad Sci U S A 99 (14): 9521-6. PMID 12093930. 

[edit] External links

v • d • e
Cell signaling, nervous tissue: neurotrophin

BDNF - CNTF - GMF - NGF - Neuregulin - NT-3 - NT-4 - PACAP

GFL: GDNF - Neurturin - Artemin - Persephin

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