GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson's disease.

Alberto Pascual,Josã© Lã³Pez-Barneo,Xavier Dâ€™Anglemont De Tassigny

doi:10.3389/fnana.2015.00010

Abstract

The glial cell line-derived neurotrophic factor (GDNF) is a well-established trophic agent for dopaminergic (DA) neurons in vitro and in vivo. GDNF is necessary for maintenance of neuronal morphological and neurochemical phenotype and protects DA neurons from toxic damage. Numerous studies on animal models of Parkinson’s disease (PD) have reported beneficial effects of GDNF on nigrostriatal DA neuron survival. However, translation of these observations to the clinical setting has been hampered so far by side effects associated with the chronic continuous intra-striatal infusion of recombinant GDNF. In addition, double blind and placebo-controlled clinical trials have not reported any clinically relevant effect of GDNF on PD patients. In the past few years, experiments with conditional Gdnf knockout mice have suggested that GDNF is necessary for maintenance of DA neurons in adulthood. In parallel, new methodologies for exogenous GDNF delivery have been developed. Recently, it has been shown that a small population of scattered, electrically interconnected, parvalbumin positive (PV+) GABAergic interneurons is responsible for most of the GDNF produced in the rodent striatum. In addition, cholinergic striatal interneurons appear to be also involved in the modulation of striatal GDNF. In this review, we summarize current knowledge on brain GDNF delivery, homeostasis, and its effects on nigrostriatal DA neurons. Special attention is paid to the therapeutic potential of endogenous GDNF stimulation in PD.

Highlights

Parkinson’s disease (PD) is a progressive, mainly idiopathic and age-related, neuronal disorder that affects as much as 1% of the population over 60 years (de Lau and Breteler, 2006)
The discovery by Lin et al (1993) of a specific DA neurotrophic factor secreted by rat glial cells -the glial cell line-derived neurotrophic factor (GDNF)- opened a new perspective for PD pathogenesis and therapy
CONCLUDING REMARKS Two decades have passed since the discovery of GDNF and much advance has been produced regarding its cellular effects and neuroprotective action on DA neurons

Summary

INTRODUCTION

Parkinson’s disease (PD) is a progressive, mainly idiopathic and age-related, neuronal disorder that affects as much as 1% of the population over 60 years (de Lau and Breteler, 2006). When added to the culture medium of midbrain-derived neural stem cells (mdNSCs), GDNF induced a DA phenotype associated with Nurr and Pitx up-regulation Transplantation of these cells into the striatum of 6-OHDA-injected rats greatly prevented the amphetamine-induced contralateral rotation in the lesioned animals (Lei et al, 2011). HGDNF-ZFP infused into the striatum of normal adult rats 4 weeks before triggering neurotoxicity by a 6-OHDA striatal injection, increased GDNF production in the striatum and improved motor activity in lesioned rats (Laganiere et al, 2010) This methodology could be potentially applicable to prevent DA neuron degeneration in genetic cases in which the disease can be diagnosed before appearance of the clinical symptoms. Such antibodies need to be tested on GDNF-KO tissue extracts as they may give false positive bands of the expected molecular size (authors’ unpublished observation), and this may contribute to overstatement on the efficiency of certain drugs in stimulating GDNF expression

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Findings

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