Glial cell line-derived neurotrophic factors (GFLs) and small molecules targeting RET receptor for the treatment of pain and Parkinson's disease

Abstract

Rearranged during transfection (RET), in complex with glial cell line-derived (GDNF) family receptor alpha (GFRα), is the canonical signaling receptor for GDNF family ligands (GFLs) expressed in both central and peripheral parts of the nervous system and also in non-neuronal tissues. RET-dependent signaling elicited by GFLs has an important role in the development, maintenance and survival of dopamine and sensory neurons. Both Parkinson's disease and neuropathic pain are devastating disorders without an available cure, and at the moment are only treated symptomatically. GFLs have been studied extensively in animal models of Parkinson's disease and neuropathic pain with remarkable outcomes. However, clinical trials with recombinant or viral vector-encoded GFL proteins have produced inconclusive results. GFL proteins are not drug-like; they have poor pharmacokinetic properties and activate multiple receptors. Targeting RET and/or GFRα with small molecules may resolve the problems associated with using GFLs as drugs and can result in the development of therapeutics for disease-modifying treatments against Parkinson's disease and neuropathic pain.

Keywords: Drug design; Drug development; GDNF family ligands (GFLs); Glial cell line-neurotrophic factor (GDNF); Neurturin (NRTN); RET agonist; RET receptor tyrosine kinase; RET receptor, artemin (ARTN); Small molecule.

Fig. 1

Neurotrophic factors and their receptors. GDNF family ligands and distant members of GFL include GDNF, NRTN, ARTN, PSPN, and GDF15. They all form homodimer and bind to respective co-receptor GFRα (1–4) and GFRΑL respectively. The complex of ligand and co-receptor interacts with RET which leads to phosphorylation of RET and activation of intracellular signalling cascades. GDNF can also signal through alternate receptor NCAM and syndecan-3 (GDNF, NRTN, and ARTN). GDNF signalling is important for survival, neurite outgrowth, migration, and differentiation of neuronal cells and regulation of body weight via appetite control

Fig. 2

Schematic representation of healthy and degenerated neurons in both Parkinson’s disease and neuropathic pain. a Dopamine neuron projections in a healthy brain are shown in the left hemisphere (yellow) and in a brain of patient with Parkinson’s disease in the right hemisphere (gray). b GFL treatments simulate regrowth and restore dopamine fibers which are shown in the right hemisphere (green). c Sensory neurons locate in dorsal root ganglia and send their projections to periphery and to spinal cord in healthy people as shown on the right panel (yellow). d In neuropathic pain patients, sensory neurons degenerate and loose terminals in both periphery and in spinal cord as shown on the right panel (gray). Treatment with GFLs protects and restores central and peripheral projections of sensory neurons and targets them to topographically correct place in the spinal cord as shown on left panel (green). Arrow heads indicate the sites of lesions in spinal nerve ligation (SNL) model of NP and dorsal root crush (DRC) model of experimental neuropathy