Glial cell line-derived neurotrophic factors (GFLs) and small molecules targeting RET receptor for the treatment of pain
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REVIEW
Glial cell line-derived neurotrophic factors (GFLs) and small molecules targeting RET receptor for the treatment of pain and Parkinson’s disease Arun Kumar Mahato 1 & Yulia A. Sidorova 1 Received: 4 March 2020 / Accepted: 27 April 2020 # The Author(s) 2020
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 Glial cell line-neurotrophic factor (GDNF) . GDNF family ligands (GFLs) . RET receptor, artemin (ARTN) . Neurturin (NRTN) . RET receptor tyrosine kinase . RET agonist . Small molecule . Drug design . Drug development
Neurotrophic factors Neurotrophic factors are a family of small secretory proteins which are necessary for survival and maintenance of both developing and mature neurons (Lanni et al. 2010). The key feature for the protein to be classified as a neurotrophic factor is the ability to promote the survival of certain neuronal population(s). Neurotrophic factors prevent neurodegeneration (Aron and Klein 2011), promote axonal growth (Kramer et al. 2006), and maintain synaptic plasticity and behavior (Lo 1995; Lewin and Barde 1996; Gómez-Palacio-Schjetnan and Escobar 2013). Neurotrophic factors are secreted into the extracellular space and, following neuronal innervation, they can be trafficked both in a retrograde and an anterograde manner
* Yulia A. Sidorova [email protected] 1
Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00014 Helsinki, Finland
(Altar and DiStefano 1998; Reynolds et al. 2000). Secreted neurotrophic factors act via receptors that are expressed in both peripheral and central nervous systems, activating intracellular signalling cascades important for neuronal survival and functioning (Chang et al. 2019). Neurotrophic factors include neurotrophins, glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), neurokines, and the mesencephalic astrocytederived neurotrophic factor/cerebral dopamine neurotrophic factor (MAN
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