Trends in Neurosciences
The coming of age of the GDNF family and its receptors: gene delivery in a rat Parkinson model may have clinical implications
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Clinical hopes and concerns
As for all newly discovered trophic factors, there is hope that GDNF might become useful in the treatment of nervous system disease. Given its spectrum of demonstrated activities which includes, but is not limited to, potent trophic actions on dopamine neurons, motoneurons and peripheral ganglia2, 9, 10, 11, 12, these hopes include treatments for Parkinson's disease, ALS, and peripheral neuropathies. Perhaps the best-studied experimental model to date in which GDNF has proven effective is that
How to increase the level of a trophic factor in the brain
In addition to the direct stereotaxic protein injection approach, there are many additional ways in which the goal of controlling the level of a trophic factor in the CNS might be achieved (see Ref. [16]). One set of techniques utilizes the protein itself: implantable, biodegradable, slow-release preparations containing the protein can be used to obtain long-term localized release. Another approach is to cross the blood-brain barrier, for instance by coupling the active protein to a molecule
Intracerebral GDNF gene delivery rescues neurons
Recently, Choi-Lundberg and colleagues[18]reported that a replication-deficient adenoviral vector carrying the human GDNF gene, when injected into the mesencephalon of rats, could protect dopamine neurons from undergoing 6-OHDA-induced degeneration. In these experiments the authors first labeled dopamine neurons by retrograde filling with fluorogold injected into the terminal areas in striatum. One week later, the DA neurotoxin 6-OHDA was injected into one striatum[19]and the ensuing loss of DA
How long will transgenes stay active?
Choi-Lundberg and colleagues measured levels of DNA, RNA and protein in mesencephalon following injections of the viral constructs and found significant amounts after one week. While GDNF protein was still detectable after four weeks by ELISA, levels of both protein and RNA (but not DNA) had dropped to about a third of the levels noted at one week. The authors therefore suggest that there had been a down-regulation of the Rous sarcoma virus promoter used to drive the expression, rather than a
Can transgene expression be directed and controlled?
In the reported experiments[18], infected cells probably included some of the DA neurons themselves, since control animals infected with lacZ and a nuclear-localizing signal had DA neurons that could be double-labeled for β-galactosidase (the product of the lacZ gene) in the nucleus, and tyrosine hydroxylase (a marker of DA neurons) in the cytoplasm. It is not known if DA neurons can utilize self-produced GDNF, but following release autocrine or paracrine effects appear likely, given the
The long and winding road to possible clinical applications
Trophic factors are characteristically very potent and always have a rather wide spectrum of effects. Therefore delivery of trophic factors in a highly localized fashion may be necessary to avoid unwanted effects. For instance, when NGF was delivered directly into putamen of patients with Parkinson's disease (to support grafts of adrenal medullary tissue) there were no noticeable side effects[15]. However, when NGF was delivered to the CSF of patients with Alzheimer's disease (to stimulate
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Cited by (40)
Involvement of integrin β1/FAK signaling in the analgesic effects induced by glial cell line-derived neurotrophic factor in neuropathic pain
2017, Brain Research BulletinCitation Excerpt :Glial cell line-derived neurotrophic factor (GDNF) is a distantly related member of the transforming growth factor-β family (Lin et al., 1993). GDNF controls the survival, growth and differentiation of distinct populations of neurons, including sensory neurons (Yan et al., 1995; Matheson et al., 1997; Olson, 1997). GDNF is expressed in the neurons of dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC).
A new alternative NF-ΚB Pathway mediated the neuroprotection of GDNF on 6-OHDA-induced da neurons neurotoxicity
2012, Brain ResearchCitation Excerpt :Subsequent reports further confirmed that GDNF could protect lesioned DA neurons in the substantia nigra pars compacta (SNc) of the midbrain (Cass, 1996; Winkler et al., 1996), and that degeneration of these neurons is the major pathological characteristic in Parkinson's disease patients. Therefore, the implication of GDNF as a potential therapeutic agent for Parkinson's disease underscores the significance of the wide range of GDNF signaling (Olson, 1997). Despite the extensive research on the biological effects of GDNF on DA neurons, the mechanisms underlying the roles of GDNF remain obscure.
Expressions and possible roles of GDNF receptors in the developing dopaminergic neurons
2010, Brain Research BulletinCitation Excerpt :The following two factors played the primary roles in the development of DA neurons, one is the neurotrophic factor, e.g. glial cell line-derived neurotrophic factor (GDNF), which has an essential effect on the survival and maturation of the DA neurons in the mammalian embryonic brain SN, and another is the cell adhesion molecule, without which cells cannot adhere to their microenvironment and will die [21,28]. GDNF, originally identified as a survival factor for midbrain DA neurons [21], can effectively protect these neurons from degeneration and death [2,8,19,24]. GDNF signaling has been known to be mediated by a receptor system consisting of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked receptor – the GDNF family receptor α1 (GFRα1), and a transmembrane signaling receptor – Ret [16,32].
GDNF signaling in embryonic midbrain neurons in vitro
2007, Brain ResearchCitation Excerpt :These mDA neurons play a central role in the pathogenesis of Parkinson's disease. Therefore GDNF has received great attention as a potential therapeutic agent for the treatment of this neurodegenerative disease (Lin et al., 1993; Lapchak et al., 1997; Olson, 1997; Grondin and Gash, 1998). GDNF promotes survival of other neurons, including subpopulations of the peripheral autonomic and sensory neurons, as well as central spinal motor, Purkinje, retinal and nor-adrenergic neurons (Lin et al., 1993; Henderson et al., 1994; Arenas et al., 1995; Buj-Bello et al., 1995; Trupp et al., 1995; Hearn et al., 1998; Heuckeroth et al., 1998; Yan et al., 1999; Mount et al., 1995).
Purified mouse dopamine neurons thrive and function after transplantation into brain but require novel glial factors for survival in culture
2005, Molecular and Cellular NeuroscienceGDNF and GFRα1 promote differentiation and tangential migration of cortical GABAergic neurons
2005, NeuronCitation Excerpt :Although the physiological consequences of a reduction in the number of inhibitory interneurons on adult brain function could not be assessed in this study, our results warrant future investigations on the possible roles of GDNF in the assembly and function of inhibitory circuits using tissue-specific mutants. Among the best-studied activities of GDNF in the brain is its ability to promote the survival of ventral midbrain dopaminergic neurons in animal models of Parkinson’s disease (Olson, 1997; Gash et al., 1998; Brundin, 2002; Kordower, 2003). Despite a voluminous literature on the effects of GDNF on dopaminergic neurons, mice lacking GDNF (or Ret, or GFRα1) display no abnormalities in dopaminergic neuron number or in the pattern or density of striatal dopaminergic innervation at birth.