GDNF synthesis, signaling, and retrograde transport in motor neurons

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.

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

“…Compared to patients without PNI (24/40, 60.0%), PDAC patients with PNI had a higher frequency of GDNF expression (16/18, 88.9%), indicating that GDNF is involved in the neural invasion process [ 26 ]. During the growth process of neurons, certain neural cells (e.g., Schwann cells and motor neurons) could secrete GDNF into extracellular space [ 27 ]. Ret proto‐oncogene (RET) is the receptor of GDNF and is selectively expressed in some PDAC cell lines (e.g., MiaPACA2, ASPC1, SW1990, and CAPAN2) [ 28 ].…”

A nuclear role for ARGONAUTE-2 in regulation of neuronal alternative polyadenylation

“…The secreted glial cell derived neurotrophic factor (GDNF) drives neurotrophic signaling that is important for axonal outgrowth, synapse maturation and neuron survival (Airaksinen & Saarma, 2002;Baudet et al, 2008;Bonanomi et al, 2012;Enomoto et al, 2001;Honma et al, 2010;Kramer et al, 2006;Pachnis et al, 1993;Runeberg-Roos & Saarma, 2007;Tuttle et al, 2019). Ret proto-oncogene is a tyrosine kinase receptor for GDNF (Romei et al, 2016) that is highly expressed in motor neurons (Baudet et al, 2008;Cintron-Colon et al, 2020;Pachnis et al, 1993). GDNF stimulation triggers RET autophosphorylation on distinct tyrosine residues, and intracellular activation of phosphatidylinositol 3-kinase (PI3-kinase) and mitogenactivated protein kinase (MAPK) pathways, which contribute to neuronal survival (Airaksinen & Saarma, 2002;Kaplan & Miller, 2000).…”

Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?

“…GDNF is a member of the TGF-β family, it was originally isolated in rat glial cells, and it promotes the differentiation and survival of dopaminergic neurons by increasing their dopamine uptake [ 29 , 30 ]. GDNF also has a neurotrophic function in motor neurons, where it enhances survival by preventing apoptosis and degeneration [ 31 , 32 , 33 , 34 , 35 , 36 ]. Because of this function, GDNF has been proposed as a therapeutic target for ALS [ 31 , 36 , 37 ].…”

“…GDNF also has a neurotrophic function in motor neurons, where it enhances survival by preventing apoptosis and degeneration [ 31 , 32 , 33 , 34 , 35 , 36 ]. Because of this function, GDNF has been proposed as a therapeutic target for ALS [ 31 , 36 , 37 ]. Its expression in the skeletal muscle of 5–7-day-old SOD1 G93A mice slowed down the progression of the disease.…”