GDNF-mediated rescue of the nigrostriatal system depends on the degree of degeneration

Abstract

Glial cell-line derived neurotrophic factor (GDNF) is a promising therapeutic molecule to treat Parkinson’s disease. Despite an excellent profile in experimental settings, clinical trials testing GDNF have failed. One of the theories to explain these negative outcomes is that the clinical trials were done in late-stage patients that have advanced nigrostriatal degeneration and may therefore not respond to a neurotrophic factor therapy. Based on this idea, we tested if the stage of nigrostriatal degeneration is important for GDNF-based therapies. Lentiviral vectors expressing regulated GDNF were delivered to the striatum of rats to allow GDNF expression to be turned on either while the nigrostriatal system was degenerating or after the nigrostriatal system had been fully lesioned by 6-OHDA. In the group of animals where GDNF expression was on during degeneration, neurons were rescued and there was a reversal of motor deficits. Turning GDNF expression on after the nigrostriatal system was lesioned did not rescue neurons or reverse motor deficits. In fact, these animals were indistinguishable from the control groups. Our results suggest that GDNF can reverse motor deficits and nigrostriatal pathology despite an ongoing nigrostriatal degeneration, if there is still a sufficient number of remaining neurons to respond to therapy.

Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson’s Disease. A Systematic Review

“…Brain study in PD patients found that SNpc cells and putamen dopaminergic terminals appear to be lost during the first 4–7 years of diagnosis. This indicates that the rescue of the nigrostriatal system mediated by GDNF relies on the degree of degeneration (Quintino et al, 2019 ). To rescue the nigrostriatal system and motor deficits, GDNF had to be present in the striatum such that a significant amount of damaged SNpc neurons remain to respond to therapy.…”

gdnf affects early diencephalic dopaminergic neuron development through regulation of differentiation‐associated transcription factors in zebrafish

“…Identification of the temporal characteristics of endogenous gdnf activation and de-activation during regeneration would offer a paradigm shift for therapeutic regulation of GDNF expression. Correct spatiotemporal application of GDNF is crucial to successfully halt or rescue neuronal deterioration resulting from neurodegenerative diseases such as PD (Eggers et al, 2019;Quintino et al, 2019).…”

Regenerative Potential of Carbon Monoxide in Adult Neural Circuits of the Central Nervous System

“…HO-1-derived astrocytic GDNF secretion reduces neuronal cell death [150]. Lentiviral vectors expressing GDNF are delivered to the striatum of rats following Parkinson's disease-like injury [151]. In the group of animals where GDNF expression is switched on during degeneration, neurons are rescued and there is a reversal of motor deficits; in contrast, in the group of animals where GDNF expression is switched on 21 d after the injury, neurons are not rescued [151].…”