Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease
Sang-Min Oh1, Mi-Yoon Chang2, Jae-Jin Song1
1Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
Abstract:
Use of the physiological mechanisms promoting midbrain DA (mDA) neuron survival seems an appropriate option for developing treatments for Parkinson's disease (PD). mDA neurons are specifically marked by expression of the transcription factors Nurr1 and Foxa2. We show herein that Nurr1 and Foxa2 interact to protect mDA neurons against various toxic insults, but their expression is lost during aging and degenerative processes. In addition to their proposed cell-autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode. As a consequence of these bimodal actions, adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission. The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy.
Insights
This study reveals that Nurr1 and Foxa2 transcription factors protect midbrain dopamine (mDA) neurons. Their gene delivery in a Parkinson
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Midbrain dopamine (mDA) neuron survival is crucial for Parkinson's disease (PD) treatment.
- Nurr1 and Foxa2 transcription factors are key markers for mDA neurons.
- Loss of Nurr1 and Foxa2 expression is linked to aging and neurodegeneration.
Purpose of the Study:
- To investigate the protective roles of Nurr1 and Foxa2 in mDA neuron survival.
- To explore the therapeutic potential of Nurr1 and Foxa2 gene delivery for Parkinson's disease.
Main Methods:
- Studied the interaction of Nurr1 and Foxa2 in protecting mDA neurons against toxic insults.
- Investigated cell-autonomous and paracrine protective effects of Nurr1 and Foxa2.
- Utilized adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model.
Main Results:
- Nurr1 and Foxa2 interact to protect mDA neurons, but their expression declines with age and disease.
- Forced expression in glia provides synergistic paracrine protection to degenerating mDA neurons.
- AAV-mediated delivery of Nurr1 and Foxa2 significantly protected mDA neurons and improved motor behaviors in a PD mouse model.
Conclusions:
- Combined gene delivery of Nurr1 and Foxa2 offers a promising therapeutic strategy for Parkinson's disease.
- The protective effects were dramatic, reproducible, and sustained for at least one year.
- Targeting Nurr1 and Foxa2 represents a viable approach for PD therapy.
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