Natriuretic peptides are neuroprotective on in vitro models of PD and promote dopaminergic differentiation of hiPSCs-derived neurons via the Wnt/\u03b2-catenin signaling

Daniela Giovannini,Federica Andreola,Simona Rossi,Annalucia Serafino,Mauro Cozzolino,Ewa Krystyna Krasnowska,Arianna Colini Baldeschi,Federica Sangiuolo,Paola Spitalieri

doi:10.1038/s41420-021-00723-6

Abstract

Over the last 20 years, the efforts to develop new therapies for Parkinson’s disease (PD) have focused not only on the improvement of symptomatic therapy for motor and non-motor symptoms but also on the discovering of the potential causes of PD, in order to develop disease-modifying treatments. The emerging role of dysregulation of the Wnt/β-catenin signaling in the onset and progression of PD, as well as of other neurodegenerative diseases (NDs), renders the targeting of this signaling an attractive therapeutic opportunity for curing this brain disorder. The natriuretic peptides (NPs) atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), are cardiac and vascular-derived hormones also widely expressed in mammalian CNS, where they seem to participate in numerous brain functions including neural development/differentiation and neuroprotection. We recently demonstrated that ANP affects the Wnt/β-catenin pathway possibly through a Frizzled receptor-mediated mechanism and that it acts as a neuroprotective agent in in vitro models of PD by upregulating this signaling. Here we provide further evidence supporting the therapeutic potential of this class of natriuretic hormones. Specifically, we demonstrate that all the three natriuretic peptides are neuroprotective for SHSY5Y cells and primary cultures of DA neurons from mouse brain, subjected to neurotoxin insult with 6-hydroxydopamine (6-OHDA) for mimicking the neurodegeneration of PD, and these effects are associated with the activation of the Wnt/β-catenin pathway. Moreover, ANP, BNP, CNP are able to improve and accelerate the dopaminergic differentiation and maturation of hiPSCs-derived neural population obtained from two differed healthy donors, concomitantly affecting the canonical Wnt signaling. Our results support the relevance of exogenous ANP, BNP, and CNP as attractive molecules for both neuroprotection and neurorepair in PD, and more in general, in NDs for which aberrant Wnt signaling seems to be the leading pathogenetic mechanism.

Highlights

Parkinson’s disease (PD) is the most common movement disorder and the second most frequent aging-related neurodegenerative disease (ND) after Alzheimer’s disease (AD)
In the last decades, increasing evidence We recently demonstrated that atrial natriuretic peptide (ANP) affects the Wnt/β-catenin suggested that the Wnt/β-catenin signaling has a critical role in midbrain dopaminergic (mDA) pathway possibly through an Fzd receptor-mediated mechanism neuron development [23, 24], and participates in adult neurogenesis [53, 54], and that it acts as a neuroprotective agent in in vitro of the hippocampus [25, 26]
Since it has been reported that nuclear localization of tyrosine hydroxylase (TH) is related to its proteasomal degradation, triggered by phosphorylation at Ser19, while the active enzyme has cytoplasmic localization [61, 62], our observations suggest that the different TH localization observed in controls and in natriuretic peptides (NPs) treated cultures could be related to catalytically inactive or catalytically active enzyme, the latter increasing during NPs-induced differentiation

Summary

INTRODUCTION

Parkinson’s disease (PD) is the most common movement disorder and the second most frequent aging-related neurodegenerative disease (ND) after Alzheimer’s disease (AD). The cleavage is all the three NPs activate the canonical Wnt signaling by operated, for ANP and BNP, by the Corin [43], a membrane- stimulating β-catenin stabilization and nuclear translocation, associated protease which includes in the extracellular region the even if with some differences in the phosphorylation kinetics of two Fzd-like cysteine-rich domains Fzd and Fzd, receptors for β-catenin and GSK for CNP (Fig. 1C, D). The effects were compared with those of ANP clinical evidence, NPs have been recently proposed as potential and with the untreated control (Fig. 2). 6-OHDA treatment innovative diagnostic and therapeutic targets for some brain consistently decreased the number of adhering cells and disorders related to a cognitive impairment such as AD [48, 51, 52]. destroyed the neurite network in SHSY5Y cells (Fig. 2A),

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DISCUSSION

MATERIALS AND METHODS

Findings

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