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

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.

Keywords: GDNF family receptor alpha 1; Parkinson’s disease; astrocyte; gene therapy; glial-cell-line-derived neurotrophic factor; microglia; neuroinflammation; rearranged during transfection.

Figure 1

Glial cell line-derived neurotrophic factor (GDNF) and GDNF receptors in a healthy brain and during disease. (A) In a healthy nervous system, GDNF expression is mainly neuronal (red). GDNF forms a complex with the GDNF family receptor alpha 1 (GFRα1), which is present in the neuronal membrane. This complex binds to RET, a transmembrane receptor, triggering an intracellular signaling cascade that promotes survival (see inset 1). A few in vitro studies have reported that GFRα1 also exists in a soluble form, suggesting that GDNF can have broader effects. However, these data lack in vivo confirmation. Some neurons express GDNF and its receptors. Therefore, a possible autocrine GDNF effect should not be excluded even though it has not been demonstrated yet. (B) Several studies report that during disease, glial cells can also express GDNF. Glial GDNF expression can promote survival and axonal growth, but sustained GDNF overexpression or ectopic GDNF expression can lead to aberrant sprouting. In pathological cases, the microglia (blue) express RET but not GFRα1, suggesting that RET signaling may occur in a GDNF-independent manner or through a GFRα1 soluble form (see inset 2). In disease conditions, GFRα1 is upregulated in astrocytes (green), but there is no evidence of RET expression (see inset 3). Further investigation is required to establish the effects of GDNF–GFRα1 astrocytic interactions.