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

Iring, András; Tóth, A.; Baranyi, Mária; Otrokocsi, Lilla; Módis, László; Gölöncsér, Flóra; Varga, B; Hortobágyi, Tibor; Bereczki, Dániel; Sperlágh, Beáta

doi:10.1016/j.phrs.2021.106045

Cited by 15 publications

(5 citation statements)

References 77 publications

(96 reference statements)

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“…Considering that P2Y receptors are associated with age‐related functional changes in other tissues (Erb et al., 2015 ; Gao et al., 2019 ; Iring et al., 2022 ; Reichenbach & Bringmann, 2016 ; Wallace et al., 2006 ), we hypothesised that they could also play a role in the altered functions of the aged cochlea. In this study, we used different mouse lines displaying varying degrees of progressive hearing loss to identify possible changes in the distribution and functional properties of P2Y receptors in the supporting cells of the ageing mouse.…”

Section: Introductionmentioning

confidence: 99%

Age‐related changes in P2Y receptor signalling in mouse cochlear supporting cells

Hool,

Jeng,

Jagger

et al. 2023

The Journal of Physiology

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Our sense of hearing depends on the function of a specialised class of sensory cells, the hair cells, which are found in the organ of Corti of the mammalian cochlea. The unique physiological environment in which these cells operate is maintained by a syncitium of non‐sensory supporting cells, which are crucial for regulating cochlear physiology and metabolic homeostasis. Despite their importance for cochlear function, the role of these supporting cells in age‐related hearing loss, the most common sensory deficit in the elderly, is poorly understood. Here, we investigated the age‐related changes in the expression and function of metabotropic purinergic receptors (P2Y1, P2Y2 and P2Y4) in the supporting cells of the cochlear apical coil. Purinergic signalling in supporting cells is crucial during the development of the organ of Corti and purinergic receptors are known to undergo changes in expression during ageing in several tissues. Immunolabelling and Ca2+ imaging experiments revealed a downregulation of P2Y receptor expression and a decrease of purinergic‐mediated calcium responses after early postnatal stages in the supporting cells. An upregulation of P2Y receptor expression was observed in the aged cochlea when compared to 1 month‐old adults. The aged mice also had significantly larger calcium responses and displayed calcium oscillations during prolonged agonist applications. We conclude that supporting cells in the aged cochlea upregulate P2Y2 and P2Y4 receptors and display purinergic‐induced Ca2+ responses that mimic those observed during pre‐hearing stages of development, possibly aimed at limiting or preventing further damage to the sensory epithelium. imageKey points Age‐related hearing loss is associated with lower hearing sensitivity and decreased ability to understand speech. We investigated age‐related changes in the expression and function of metabotropic purinergic (P2Y) receptors in cochlear non‐sensory supporting cells of mice displaying early‐onset (C57BL/6N) and late‐onset (C3H/HeJ) hearing loss. The expression of P2Y1, P2Y2 and P2Y4 receptors in the supporting cells decreased during cochlear maturation, but that of P2Y2 and P2Y4 was upregulated in the aged cochlea. P2Y2 and P2Y4 receptors were primarily responsible for the ATP‐induced Ca2+ responses in the supporting cells. The degree of purinergic expression upregulation in aged supporting cells mirrored hearing loss progression in the different mouse strains. We propose that the upregulation of purinergic‐mediated signalling in the aged cochlea is subsequent to age‐related changes in the hair cells and may act as a protective mechanism to limit or to avoid further damage to the sensory epithelium.

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Section: Introductionmentioning

confidence: 99%

Age‐related changes in P2Y receptor signalling in mouse cochlear supporting cells

Hool,

Jeng,

Jagger

et al. 2023

The Journal of Physiology

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“…The Ras homolog gene family protein A (RhoA)/Rho-associated coil-coil containing protein kinase (ROCK) pathway is involved in various physiological activities of cells, including cytoskeleton reconstruction, contraction, migration, phagocytic adhesion, stress ber formation, the in ammatory response, and angiogenesis, and recent studies have found it to be closely related to the polarization of microglia [23,24] . Targeting the inhibition of the RhoA/ROCK signaling pathway has gradually become the most promising direction for the treatment of TBI, and multiple molecules, such as Nogo, CSPG, and glutamate, may be upstream molecules of this pathway [25] .…”

Section: Discussionmentioning

confidence: 99%

Piezo2 contributes to traumatic brain injury by activating the RhoA/ROCK1 pathways

Xiao,

Zhang,

Yuan

et al. 2023

Preprint

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Traumatic brain injury (TBI) can lead to short-term and long-term physical and cognitive impairments, which have significant impacts on patients, families, and society. Currently, treatment outcomes for this disease are often unsatisfactory, due at least in part to the fact that the molecular mechanisms underlying the development of TBI are largely unknown. Here, we observed significant upregulation of Piezo2, a key mechanosensitive ion channel protein, in the injured brain tissue of a mouse model of TBI induced by controlled cortical impact. Pharmacological inhibition and genetic knockdown of Piezo2 after TBI attenuated neuronal death, brain edema, brain tissue necrosis, and deficits in neural function and cognitive function. Mechanistically, the increase in Piezo2 expression contributed to TBI-induced neuronal death and subsequent production of TNF-α and IL-1β, likely through activation of the RhoA/ROCK1 pathways in the central nervous system. Our findings suggest that Piezo2 is a key player in and a potential therapeutic target for TBI.

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“…P2RY12 expression decreases as microglia migrate and undergo a shift to an amoeboid state, increasing phagocytic and secretory activities [81]. In some neurodegenerative diseases, P2RY12 can be associated with activated, inflammatory microglia [81,82], but in the context of prion disease, both P2RY12 and TMEM119 are shown to decrease over the course of infection [30,34]. Changes in microglia are first detectable in the thalamus at preclinical stages, and cell morphology shifts from being ramified to activated or amoeboid.…”

Section: Dam! Look At All Those Microgliamentioning

confidence: 99%

The Role of Glial Cells in Neurobiology and Prion Neuropathology

Hay,

Popichak,

Moreno

et al. 2024

Cells

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Prion diseases are rare and neurodegenerative diseases that are characterized by the misfolding and infectious spread of the prion protein in the brain, causing progressive and irreversible neuronal loss and associated clinical and behavioral manifestations in humans and animals, ultimately leading to death. The brain has a complex network of neurons and glial cells whose crosstalk is critical for function and homeostasis. Although it is established that prion infection of neurons is necessary for clinical disease to occur, debate remains in the field as to the role played by glial cells, namely astrocytes and microglia, and whether these cells are beneficial to the host or further accelerate disease. Here, we review the current literature assessing the complex morphologies of astrocytes and microglia, and the crosstalk between these two cell types, in the prion-infected brain.

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

Cited by 15 publications

References 77 publications

Age‐related changes in P2Y receptor signalling in mouse cochlear supporting cells

Age‐related changes in P2Y receptor signalling in mouse cochlear supporting cells

Piezo2 contributes to traumatic brain injury by activating the RhoA/ROCK1 pathways

The Role of Glial Cells in Neurobiology and Prion Neuropathology

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