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GDNF Therapy: Can We Make It Work?

Anders Björklund1

  • 1Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.

Journal of Parkinson'S Disease
|May 3, 2021
PubMed
Summary

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.
Keywords:
Nurr1Parkinson’s diseaseRetneurturinphospho-S6

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  • 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.