The dualistic role of the purinergic P2Y12-receptor in an in vivo model of Parkinson's disease: Signalling pathway and novel therapeutic targets

Beáta Sperlágh,Lilla Otrokocsi,Mária Baranyi,Flóra Gölöncsér,Adrián Tóth,Tibor Hortobágyi,Ádám Dénes,Bernadett Varga,László V Módis,Dániel Bereczki,András Iring

doi:10.1016/j.phrs.2021.106045

Abstract

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative condition; characterized with the degeneration of the nigrostriatal dopaminergic pathway and neuroinflammation. During PD progression, microglia, the resident immune cells in the central nervous system (CNS) display altered activity, but their role in maintaining PD development has remained unclear to date. The purinergic P2Y12-receptor (P2Y12R), which is expressed on the microglia in the CNS has been shown to regulate microglial activity and responses; however, the function of the P2Y12R in PD is unknown. Here we show that MPTP-induced PD symptoms in mice are associated with marked neuroinflammatory changes and P2Y12R contribute to the activation of microglia and progression of the disease. Surprisingly, while pharmacological or genetic targeting of the P2Y12R augments acute mortality in MPTP-treated mice, these interventions protect against the neurodegenerative cell loss and the development of neuroinflammation in vivo. Pharmacological inhibition of receptors during disease development reverses the symptoms of PD and halts disease progression. We found that P2Y12R regulates ROCK and p38 MAPK activity and control cytokine production. Our principal finding is that the receptor has a dualistic role in PD: functional P2Y12Rs are essential to initiate a protective inflammatory response, since the lack of the receptor leads to reduced survival; however, at later stages of neurodegeneration, P2Y12Rs are apparently responsible for maintaining the activated state of microglia and stimulating pro-inflammatory cytokine response. Understanding protective and detrimental P2Y12R-mediated actions in the CNS may reveal novel approaches to control neuroinflammation and modify disease progression in PD.

Highlights

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease [1]
We have observed that genetic deletion or pharmacological blockade of the re ceptor contributes to lower survival following MPTP-treatment (Fig. 1A and Supplementary Fig. 1A)
We have previously showed that P2Y12R regulate hyperalgesia and local inflammatory processes, and contribute to the develop ment of chronic hindpaw inflammation [9]; while P2Y12R located on microglia affect neuropathic pain via GTP-Small GTPase Ras homolog family member A (RhoA)/ROCK pathway and p38 p38 mitogen-activated protein kinase (MAPK) activation after spinal cord injury [68]

Summary

Introduction

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease [1]. The incidence of new Parkinson’s cases ranges from 5 to 15 in 100,000 annually [2], most prominently during the sixth to ninth decades of life. Quality of life and present increased mortality risks [3,4]; symptoms that include motor function impairments, such as asymmetric tremor, cogwheel rigidity, bradykinesia, as well as non-motor features, including constipation, depression and sleep disorder [2]. Characteristic pathological feature of PD is the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta and deposition of insoluble α-synuclein. While both genetic and environmental factors influence disease development, they converge on common pathways to induce PD. These pathways include mitochondrial dysfunction, oxidative stress, impaired autophagy, protein aggregation and neuroinflammation [5]

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Conclusion