GDNF synthesis, signaling, and retrograde transport in motor neurons
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REVIEW
GDNF synthesis, signaling, and retrograde transport in motor neurons Alberto F. Cintrón-Colón 1 & Gabriel Almeida-Alves 1 & Alicia M. Boynton 1 & John M. Spitsbergen 1 Received: 17 May 2020 / Accepted: 18 August 2020 # The Author(s) 2020
Abstract Glial cell line–derived neurotrophic factor (GDNF) is a 134 amino acid protein belonging in the GDNF family ligands (GFLs). GDNF was originally isolated from rat glial cell lines and identified as a neurotrophic factor with the ability to promote dopamine uptake within midbrain dopaminergic neurons. Since its discovery, the potential neuroprotective effects of GDNF have been researched extensively, and the effect of GDNF on motor neurons will be discussed herein. Similar to other members of the TGF-β superfamily, GDNF is first synthesized as a precursor protein (pro-GDNF). After a series of protein cleavage and processing, the 211 amino acid pro-GDNF is finally converted into the active and mature form of GDNF. GDNF has the ability to trigger receptor tyrosine kinase RET phosphorylation, whose downstream effects have been found to promote neuronal health and survival. The binding of GDNF to its receptors triggers several intracellular signaling pathways which play roles in promoting the development, survival, and maintenance of neuron-neuron and neuron-target tissue interactions. The synthesis and regulation of GDNF have been shown to be altered in many diseases, aging, exercise, and addiction. The neuroprotective effects of GDNF may be used to develop treatments and therapies to ameliorate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this review, we provide a detailed discussion of the general roles of GDNF and its production, delivery, secretion, and neuroprotective effects on motor neurons within the mammalian neuromuscular system. Keywords GDNF signaling . GDNF . Motor neuron
Introduction Neurotrophic factors (NTFs) are a class of proteins that promote neuronal survival, control cell proliferation and differentiation, are required for axonal and dendritic elaborations, and regulate synaptic plasticity (Yan et al. 1995; Henderson et al. 1994; Zhu et al. 2008). NTFs include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4) belonging to the neurotrophins family, ciliary neurotrophic factor belonging to the CNTF family, and our neurotrophic factor of interest, glial cell line–derived neurotrophic factor (GDNF) belonging to the GDNF family ligands (GFLs) (Cobianchi et al. 2017; Oppenheim et al. 1995). One of the main functions of neurotrophic factors is to act as neurocytokines and, upon * John M. Spitsbergen [email protected] 1
Department of Biological Sciences, Western Michigan University, Kalamazoo, MI 49008, USA
synthesis and secretion, to facilitate communication between neurons and their target tissues (Morcuende et al. 2013). GFLs have four members: GDNF, neurturin, persephin, and artemin. The members of this family have low amino acid sequence homology,
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