Role of Receptor Protein Tyrosine Phosphatase β/ζ in Neuron-Microglia Communication in a Cellular Model of Parkinson's Disease.

Marta Del Campo,Gonzalo Herradon,Marta Vicente-Rodríguez,Esther Gramage,Sara Martín Martínez,María Haro,Rosalía Fernández-Calle,José María Zapico

doi:10.3390/ijms22136646

Marta Del Campo, Gonzalo Herradon + Show 6 more

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https://doi.org/10.3390/ijms22136646

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Abstract

Pleiotrophin (PTN) is a neurotrophic factor that regulates glial responses in animal models of different types of central nervous system (CNS) injuries. PTN is upregulated in the brain in different pathologies characterized by exacerbated neuroinflammation, including Parkinson’s disease. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is abundantly expressed in the CNS. Using a specific inhibitor of RPTPβ/ζ (MY10), we aimed to assess whether the PTN/RPTPβ/ζ axis is involved in neuronal and glial injury induced by the toxin MPP+. Treatment with the RPTPβ/ζ inhibitor MY10 alone decreased the viability of both SH-SY5Y neuroblastoma cells and BV2 microglial cultures, suggesting that normal RPTPβ/ζ function is involved in neuronal and microglial viability. We observed that PTN partially decreased the cytotoxicity induced by MPP+ in SH-SY5Y cells underpinning the neuroprotective function of PTN. However, MY10 did not seem to modulate the SH-SY5Y cell loss induced by MPP+. Interestingly, we observed that media from SH-SY5Y cells treated with MPP+ and MY10 decreases microglial viability but may elicit a neuroprotective response of microglia by upregulating Ptn expression. The data suggest a neurotrophic role of microglia in response to neuronal injury through upregulation of Ptn levels.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss in the substantia nigra and intraneural aggregation of alpha-synuclein in Lewy bodies
We aimed to study the consequences of the modulation of the PTN/RPTPβ/ζ signaling pathway and its possible influence in neuron-microglia communication using a well-studied acute MPP+ in vitro model of PD, the endogenous inhibitor of RPTPβ/ζ, PTN, and the selective small-molecule inhibitor of RPTPβ/ζ, MY10
Pleiotrophin a known modulatorcommunication of neuroinflammation expressed in t axis plays a role in the glial responses associated with PD remains unknown

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss in the substantia nigra and intraneural aggregation of alpha-synuclein in Lewy bodies. The pathophysiology of PD is complex and multifactorial and different pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress and apoptosis may underlie nigrostriatal dopaminergic neuronal degeneration [1,2]. The neuroimmune component in PD has gained attention from the extensive data collected from cell culture, animal models, and postmortem analyses of human PD brains, establishing a dynamic contribution of chronic, sustained neuroinflammation to neuronal degeneration in the early stages of PD [3]. Microglia can be activated by various stimuli such as neuronal death, mechanical injury, or toxins, and they contribute to tissue homeostasis by promoting the elimination of pathogens, dead cells, or other cellular debris [4].

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