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.
Highlights
Parkinson’s disease (PD) is a common movement disorder prevalent in older persons
These findings collectively suggest an interplay between Nurr1 and Foxa2 that promotes midbrain DA (mDA) neuron functions in the adult midbrain, like those seen in the developing midbrain (Lee et al, 2010; Stott et al, 2013; Yi et al, 2014)
Consistent with this, we found that forced expression of Nurr1 in BV2 microglia led to a significant reduction in the expression of the pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), inducible nitric oxide (NO) synthase, and interleukin-1b (IL-1b) upon exposure to the Toll-like receptor 4 (TLR4) ligand, lipopolysaccharide (LPS) (Fig 4A, upper)
Summary
The pathophysiologic feature of PD is progressive degeneration of dopamine (DA)-secreting neurons (DA neurons) in the substantia nigra (SN) of the midbrain, which results in loss of nigrostriatal DA neurotransmission. Midbrain DA (mDA) neurons in the SN are vulnerable to oxidative stress because of their reduced levels of the antioxidant glutathione and increased nigral iron content (Dexter et al, 1989; Sian et al, 1994). Chronic inflammation underlies PD pathology, and a number of PD risk factors such as environmental toxins, heavy metals, head trauma, and bacterial or viral infections are underpinned by inflammation (Wirdefeldt et al, 2011). Inflammatory reactions induce the production of ROS, and the reverse occurs. A feed-forward cycle of ROS production and inflammation underlies DA neuronal cell death in idiopathic PD
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