Signalling and Receptors of GDNF

GDNF receptors

The Glial cell line-Derived Neurotrophic Factor (GDNF) was originally found when searching for a neurotrophic factor which would prevent the continued degeneration of midbrain dopaminergic neurons—a hallmark of Parkinson’s disease [1-2]. Although GDNF was identified, cloned, and characterized based on its ability to promote the survival and dopamine uptake of dissociated rat embryonic midbrain cultures, this protein soon turned out to be very broadly expressed, as well as crucially important for the development of especially the enteric nervous system, kidney, and regulating spermatogenesis. GDNF is now known as a multifunctional protein with the capacity to induce cellular survival, proliferation, migration, and differentiation.

The therapeutic potential of GDNF triggered interest in searching for homologous proteins. GDNF became the founding member of a small subfamily, GDNF family ligands (GFLs). This family consists of four highly homologous proteins: GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). All GFLs signal through the same transmembrane receptor, tyrosine kinase REarranged during Transfection (RET), but GFLs can activate RET only in the presence of a co-receptor—GDNF Family Receptor α (GFRα). Specificity arises through the preferential binding of each GFL to one of four GFRα1-4 co-receptors. Upon activation, RET is transphosphorylated and triggers complex intracellular signaling cascades. Recently, a fifth member of the family called GDF15 was shown to bind GFRα-like receptor GFRAL and activate RET [3].

We are interested in the structure and signaling of GFLs and their receptor complexes [4-5]. We also have characterized how ProGDNF is modified, processed [6], and secreted [7]. When searching for new receptors for GFLs we identified Syndecan-3 [8] as the binding and signaling receptor, and SorlLA as a sorting receptor, for the GDNF/GFRα1 complex [9]. Our studies on GFLs and their receptors have also shed light on their complex downstream signaling [10-11], as well as their diverse biological functions in drosophila and mouse animal models [12-14].

This work has led us to develop RET agonists [15], as well as biologically active, new NRTN variants with decreased binding to heparin and improved spreading in the tissue for the treatment of Parkinson’s disease [16].

References:

  1. Airaksinen, MS. and Saarma, M. (2002) The GDNF family: receptor mechanisms, biological functions and therapeutic utility. Nature Rev. Neurosci., 3(5):383-94. 10.1038/nrn812
  2. Bespalov, M., and Saarma M. (2007) GDNF receptor complex is an emerging drug target. Trends in Pharmacological Sciences 28(2), 68-74. 10.1016/j.tips.2006.12.005
  3. Saarma M, Goldman A. (2017) Obesity: Receptors identified for a weight regulator. Nature. 550 (7675):195-197. doi: 10.1038/nature24143 10.1038/nature24143
  4. Leppänen, V.-M., et al., (2004) The structure of GFRa1 domain 3 reveals a novel fold and new insights into GDNF binding and RET activation. EMBO J., 23(7):1452-62. 10.1038/sj.emboj.7600174
  5. Parkash, V., et al., (2008) The Structure of the glial cell line-derived neurotrophic factor-coreceptor complex. Insights into RET signalling and heparin binding.  J Biol Chem, 283, (50):35164-72. 10.1074/jbc.M802543200
  6. Piccinini, E., et al., (2013) Glial cell line-Derived Neurotrophic Factor: characterization of mammalian posttranslational modifications. Ann Med, 45(1):66-73. 10.3109/07853890.2012.663927
  7. Lonka-Nevalaita, L., et al., (2010) Characterization of the intracellular localization, processing and secretion of two GDNF splice isoforms. J. Neurosci. 30(34):11403-13. 10.1523/JNEUROSCI.5888-09.2010
  8. Bespalov M. M., et al., (2011) Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin and artemin. J. Cell Biol., 192(1):153-69. 10.1083/jcb.201009136
  9. Glerup, S., et al., (2013) SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET. Cell Rep. 3(1):186-99. 10.1016/j.celrep.2012.12.011
  10. Yu, L.Y., et al., (2003) GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway. J Cell Biol. 163(5):987-97. 10.1083/jcb.200305083
  11. Runeberg-Roos, P., et al., (2007) RET(MEN 2B) is active in the endoplasmic reticulum before reaching the cell surface. Oncogene. 26:7909-15. 10.1038/sj.onc.1210591
  12. Kallijärvi, J., et al., (2012) Characterization of Drosophila GDNF receptor-like and evidence for its evolutionarily conserved interaction with neural cell adhesion molecule (NCAM)/FasII. PLoS One 7(12):e51997. 10.1371/journal.pone.0051997
  13. Ihermann-Hella, A., et al., (2014) Mitogen-activated protein kinase (MAPK) pathway regulates branching by remodeling epithelial cell adhesion. PLoS Genet. 10(3):e1004193. 10.1371/journal.pgen.1004193
  14. Kopra, J., et al., (2015) GDNF is not required for catecholaminergic neuron survival in vivo. Nat Neurosci. 18(3):319-22. 10.1038/nn.3941
  15. Sidorova, Y. A., et al., (2017) A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat. Front Pharmacol. 8:365. 10.3389/fphar.2017.00365
  16. Runeberg-Roos, P., et al., (2016) Developing therapeutically more efficient Neurturin variants for treatment of Parkinson's disease. Neurobiol Dis. 96:335-45. 10.1016/j.nbd.2016.07.008