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GDNF Therapy: Can We Make It Work?
1Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
Abstract:
In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson's disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall markedly reduced relative to the non-PD controls, and most severely, up to 80%, in nigral neurons containing α-synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of the remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8-10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This "wind-up" mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved.
Insights
Parkinson's disease (PD) patients show reduced Ret receptor levels in neurons with alpha-synuclein inclusions. However, NRTN gene therapy may restore Ret expression and signaling, offering therapeutic potential.
Area of Science:
- Neuroscience
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons.
- Glial cell line-derived neurotrophic factor (GDNF) and Neurturin (NRTN) signaling pathways are implicated in neuronal survival and function.
- Previous studies suggested limited restorative effects of GDNF/NRTN therapy in PD patients.
Purpose of the Study:
- To investigate the status of GDNF/NRTN signaling, specifically the Ret receptor, in postmortem brain tissue of Parkinson's disease patients.
- To explore the potential of NRTN gene therapy to restore Ret expression and signaling in PD.
Main Methods:
- Postmortem analysis of nigral neurons from PD patients and non-PD controls.
- Assessment of Ret receptor levels and downstream signaling.
- Examination of brain tissue from patients who received AAV-NRTN gene therapy years prior.
Main Results:
- Marked reduction (up to 80%) in Ret receptor levels in nigral neurons with alpha-synuclein inclusions in PD patients compared to controls.
- Impaired downstream signaling of the Ret receptor in these neurons.
- Evidence suggesting NRTN therapy can restore Ret expression and upregulate its signaling pathway, potentially via interaction with Nurr1.
Conclusions:
- GDNF/NRTN signaling is compromised in Parkinson's disease, particularly in neurons affected by alpha-synuclein pathology.
- NRTN gene therapy shows potential for a "wind-up" mechanism to restore Ret signaling, offering therapeutic promise for PD.
- Further research and optimized dosing are needed to overcome challenges and realize the full therapeutic potential of GDNF/NRTN therapy in Parkinson's disease.
