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 .
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 , and secreted . When searching for new receptors for GFLs we identified Syndecan-3  as the binding and signaling receptor, and SorlLA as a sorting receptor, for the GDNF/GFRα1 complex . 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 , 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 .
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- 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
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