GDNF, A Neuron-Derived Factor Upregulated in Glial Cells during Disease.

Marcelo Duarte Azevedo,Sibilla Sander,Liliane Tenenbaum

doi:10.3390/jcm9020456

Abstract

In a healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons, and, in some instances, it has also been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex with the GDNF family receptor α1 (GFRα1), which is mainly expressed by neurons and can act in cis as a membrane-bound factor or in trans as a soluble factor. The GDNF/GFRα1 complex signals through interactions with the “rearranged during transfection” (RET) receptor or via the neural cell adhesion molecule (NCAM) with a lower affinity. GDNF can also signal independently from GFRα1 by interacting with syndecan-3. RET, which is expressed by neurons involved in several pathways (nigro–striatal dopaminergic neurons, motor neurons, enteric neurons, sensory neurons, etc.), could be the main determinant of the specificity of GDNF’s pro-survival effect. In an injured brain, de novo expression of GDNF occurs in glial cells. Neuroinflammation has been reported to induce GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive reactive astrocytes, and neuron/glia (NG2) positive microglia-like cells. This disease-related GDNF overexpression can be either beneficial or detrimental depending on the localization in the brain and the level and duration of glial cell activation. Some reports also describe the upregulation of RET and GFRα1 in glial cells, suggesting that GDNF could modulate neuroinflammation.

Highlights

Glial cell line-derived neurotrophic factor (GDNF) has been isolated from the conditioned media of a rat glioma cell line on the basis of its trophic activity towards primary cultures of dopaminergic neurons [1].Following the administration of GDNF family ligands (GFL) in animals, neurorestorative effects have been demonstrated in models of several neurological diseases [2,3,4]
In the 6-hydroxydopamine (6-OHDA) Parkinson’s disease (PD) model, around 60% of surviving tyrosine hydroxylase (TH)-positive neurons were located near neuron-glial antigen 2 (NG2) cells that expressed GDNF [47]
GDNF binding to heparan sulfate has been shown to be beneficial for the protection of dopaminergic neurons in the 6-OHDA rat model of PD [71]

Summary

Introduction

Glial cell line-derived neurotrophic factor (GDNF) has been isolated from the conditioned media of a rat glioma cell line on the basis of its trophic activity towards primary cultures of dopaminergic neurons [1]. In a healthy adult brain, GDNF expression decreases and is restricted to specific regions: the cortex, hippocampus, striatum, substantia nigra This discrepancy could be explained by the differences between the probes used for in situ hybridization, the sensitivity of the method (digoxygenin-labeled versus radiolabeled probes), and the sex of the animals (female versus male)), thalamus, cerebellum, and spinal cord [20,21,22]. For clarity, we will focus on the expression of GDNF and its receptors in the nervous system in vivo, except for some aspects that have only been addressed in vitro

Glial Cells Express GDNF during Disease

Glial Cells Express GDNF Receptors during Disease

Findings

Methods