Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease

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. image Gene therapy of Nurr1 and Foxa2 protects midbrain dopamine ( mDA ) neurons from degeneration in a mouse model of Parkinson's disease ( PD ), suggesting that exploitation of the physiological mechanisms promoting mDA neuron survival might be an option for developing treatments for PD. Nurr1 and Foxa2 are specifically expressed in mDA neurons of adult mouse midbrain and synergistically interact to promote neuronal survival. Nurr1 and Foxa2 protein expression is lost in mDA neurons during aging and degenerative processes. Forced expression of Nurr1 and Foxa2 protects mDA neurons from various toxic insults in vitro and in vivo , and relieved motor deficits associated with mDA neuronal loss in the PD mouse model. In addition to cell‐autonomous actions in mDA neurons, combined Nurr1+Foxa2 transgene expression in glial cells creates a neuroprotective environment by suppressing the secretion of pro‐inflammatory cytokines as well as promoting the release of neurotrophic factors.