Absolute requirement of GDNF for adult catecholaminergic neuron survival

Abstract

GDNF is a potent neurotrophic factor that protects catecholaminergic neurons from toxic damage and induces fiber outgrowth. However, the actual role of endogenous GDNF in the normal adult brain is unknown, even though GDNF-based therapies are considered promising for neurodegenerative disorders. We have generated a conditional GDNF-null mouse to suppress GDNF expression in adulthood, hence avoiding the developmental compensatory modifications masking its true physiologic action. After Gdnf ablation, mice showed a progressive hypokinesia and a selective decrease of brain tyrosine hydroxylase (Th) mRNA, accompanied by pronounced catecholaminergic cell death, affecting most notably the locus coeruleus, which practically disappears; the substantia nigra; and the ventral tegmental area. These data unequivocally demonstrate that GDNF is indispensable for adult catecholaminergic neuron survival and also show that, under physiologic conditions, downregulation of a single trophic factor can produce massive neuronal death.

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

“…GDNF may be involved in postnatal DA SNpc maintenance (Kopra et al, 2015; Pascual & López‐Barneo, 2015; Pascual et al, 2008). Although FS are the main producers of striatal GDNF, ACh marginally contribute to its expression (Hidalgo‐Figueroa et al, 2012).…”

“…We define three parallel and interdependent neurotrophic relationships characterized by (a) a bidirectional relation between DA SNpc and FS which may involve GDNF (Hidalgo‐Figueroa et al, 2012; Kopra et al, 2015; Pascual & López‐Barneo, 2015; Pascual et al, 2008); (b) a unidirectional relation between ACh and DA SNpc that does not involve GDNF; and (c) a dependence of ACh survival on Shh that not exclusively requires the DA SNpc but may imply FS and ACh (Figure 5d).…”

“…Brain was removed and immediately frozen in liquid nitrogen. Hemicortex and striatum were processed as described (Pascual et al, 2008). Absorbance from hemicortical sample extracts was subtracted to each individual striatal measurement.…”

“…Modulatory striatal interneurons are engaged in reciprocal neurotrophic relationships with DA SNpc (Figure 1a). Adult FS and some striatal ACh produce glial cell line‐derived neurotrophic factor (GDNF; Hidalgo‐Figueroa, Bonilla, Gutiérrez, Pascual, & López‐Barneo, 2012), a potent dopaminotrophic factor required for survival and functionality of DA SNpc (Ibáñez & Andressoo, 2016; Kumar et al, 2015; Pascual et al, 2008). However, the role of GDNF in adult SNpc survival is still controversial (Kopra et al, 2015; Pascual & López‐Barneo, 2015) and needs further clarification.…”

Transgenic Expression of Human Glial Cell Line-Derived Neurotrophic Factor from Integration-Deficient Lentiviral Vectors is Neuroprotective in a Rodent Model of Parkinson's Disease

“…GDNF exerts its effects by regulating cell survival and cell differentiation through PI3K/Akt and Ras/ERK pathways (Toth et al, 2002). The potential neuroprotection and neurorestoration effects of GDNF have been examined in both rodent and nonhuman primate models of PD with positive effects shown in a variety of them Eslamboli et al, 2003;Pascual et al, 2008). These encouraging results then prompted initial open-label clinical trials, which suggested that continuous delivery of GDNF (or its relative, neurturin) by protein infusion or viral vectormediated delivery was efficacious in advanced PD patients (Gill et al, 2003;Marks et al, 2008).…”