Abstract
In the last decades increasing evidence indicated a crucial role of the Wnt/β-catenin signaling in development of midbrain dopaminergic (mDA) neurons. Recently dysregulation of this pathway has been proposed as a novel pathomechanism leading to Parkinson’s disease (PD) and some of the molecules participating to the signaling have been evaluated as potential therapeutic targets for PD. Atrial natriuretic peptide (ANP) is a cardiac-derived hormone having a critical role in cardiovascular homeostasis. ANP and its receptors (NPRs) are widely expressed in mammalian central nervous system (CNS) where they could be implicated in the regulation of neural development, synaptic transmission and information processing, as well as in neuroprotection. Until now, the effects of ANP in the CNS have been mainly ascribed to the binding and activation of NPRs. We have previously demonstrated that ANP affects the Wnt/β-catenin signaling in colorectal cancer cells through a Frizzled receptor-mediated mechanism. The purpose of this study was to investigate if ANP is able to exert neuroprotective effect on two in vitro models of PD, and if this effect could be related to activation of the Wnt/β-catenin signaling. As cellular models of DA neurons, we used the proliferating or RA-differentiated human neuroblastoma cell line SH-SY5Y. In both DA neuron-like cultures, ANP is able to positively affect the Wnt/β-catenin signaling, by inducing β-catenin stabilization and nuclear translocation. Importantly, activation of the Wnt pathway by ANP exerts neuroprotective effect when these two cellular systems were subjected to neurotoxic insult (6-OHDA) for mimicking the neurodegeneration of PD. Our data support the relevance of exogenous ANP as an innovative therapeutic molecule for midbrain, and more in general for brain diseases for which aberrant Wnt signaling seems to be involved.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra (Hornykiewicz, 1975)
SHSY5Y cells in basal condition (SHSY5Ywt) have been characterized for the expression and intracellular distribution of neuronal markers (Nestin, Tubulin-β3, NeuN) and of the DA neuron specific markers tyrosine hydroxylase (TH) and nuclear receptor related 1 protein (Nurr1), and of two crucial molecules participating to the Wnt/β-catenin signaling, the Frizzled-1 receptor (Fzd1) receptor and β-catenin (Figure 1)
Even if proliferating and retinoic acid (RA)-differentiated SHSY5Y cells have long been used for studies in neuroscience as models of DA neurons, data reported in literature about which of the two systems is the most suitable model for investigating the molecular and cellular mechanisms underlying the pathophysiology of PD are often inconsistent (Cheung et al, 2009; Lopes et al, 2010, 2017; Xie et al, 2010)
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive degeneration of mDA neurons in the substantia nigra (Hornykiewicz, 1975). There is no cure for PD, and treatments for this disease mostly consist in pharmacotherapy to restore striatal dopamine levels, that only temporary reduce symptoms (Olanow and Schapira, 2013). In this context, deepening of knowledge on molecular mechanisms underlying PD insurgence and progression is crucial for discovering innovative molecular targets useful for developing more effective therapeutic strategies. Numerous studies have been published, that aimed to identify innovative PD biomarkers, useful as therapeutic targets, and to demonstrate the neuroprotective role of endogenous and exogenous molecules (Chen et al, 2015; Price et al, 2015; Wang et al, 2017; Zou et al, 2017)
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