Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

Parcq, Jérôme; Bertrand, Thomas; Montagne, Axel; Baron, Amandine; Macrez, Richard; Billard, J.M.; Briens, Aurélien; Hommet, Yannick; Wu, Jialing; Yepes, Manuel; Lijnen, H. Roger; Dutar, P.; Anglès-Cano, Eduardo; Vivien, Denis

doi:10.1038/cdd.2012.86

Cited by 58 publications

(50 citation statements)

References 41 publications

(61 reference statements)

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“…44 Things seem more complex, as depending of its form, its dose, and its localization tPA can display pro-survival effects on neurones. 21,45 For example, tPA is neuroprotective in a model of glucose privation 46 and a model of cerebral ischaemia, 47 and this effect required NMDA receptors. At the first look, it could seem contradictory with previous findings where tPA interaction with NMDA receptors was detrimental in stroke.…”

Section: Discussionmentioning

confidence: 99%

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

et al. 2017

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The unfolded protein response (UPR) is an endoplasmic reticulum (ER) -related stress conserved pathway that aims to protect cells from being overwhelmed. However, when prolonged, UPR activation converts to a death signal, which relies on its PERK-eIF2α branch. Overactivation of the UPR has been implicated in many neurological diseases, including cerebral ischaemia. Here, by using an in vivo thromboembolic model of stroke on transgenic ER stress-reporter mice and neuronal in vitro models of ischaemia, we demonstrate that ischaemic stress leads to the deleterious activation of the PERK branch of the UPR. Moreover, we show that the serine protease tissue-type plasminogen activator (tPA) can bind to cell surface Grp78 (78 kD glucose-regulated protein), leading to a decrease of the PERK pathway activation, thus a decrease of the deleterious factor CHOP, and finally promotes neuroprotection. Altogether, this work highlights a new role and a therapeutic potential of the chaperone protein Grp78 as a membrane receptor of tPA capable to prevent from ER stress overactivation.

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Section: Discussionmentioning

confidence: 99%

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

et al. 2017

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“…For example, studies have suggested that a primary role of tPA in the CNS is direct regulation of neuronal activity through its action on the NMDA receptor and neuronal calcium signaling. 20 , 21 , 74 It is conceivable, however, that tPA-induced changes in BBB permeability could lead to a loss of precise control of the extracellular environment, which in turn, could promote dysregulation of neuronal signaling pathways such as the NMDA pathway. Likewise, tPA has been suggested to directly promote excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Identification of a neurovascular signaling pathway regulating seizures in mice

Fredriksson

Stevenson

et al. 2015

Ann Clin Transl Neurol

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ObjectiveA growing body of evidence suggests that increased blood–brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.MethodsAn experimental model of kainate-induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA−/−), its inhibitor neuroserpin (Nsp−/−), or both (Nsp:tPA−/−), and in mice conditionally deficient in the platelet-derived growth factor receptor alpha (PDGFRα).ResultsCompared to wild-type (WT) mice, Nsp−/− mice have significantly reduced latency to seizure onset and generalization; whereas tPA−/− mice have the opposite phenotype, as do Nsp:tPA−/− mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure-resistant tPA−/− mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPA−/−, and Nsp−/− mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFRα on perivascular astrocytes.InterpretationTogether, these data identify a specific molecular pathway involving tPA-mediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.

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“…For example, tPA may enhance NMDA-R mediated calcium influx and activate the ERK isoform of MAPK to cause neurotoxicity. 27–32 However, additional studies are needed to establish the exact role of wt-tPA neurotoxicity in the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Tissue-Type Plasminogen Activator-A ^296–299 Prevents Impairment of Cerebral Autoregulation After Stroke Through Lipoprotein-Related Receptor–Dependent Increase in cAMP and p38

Armstead

Riley

Yarovoi

et al. 2016

Stroke

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Background and Purpose The sole FDA approved treatment for stroke is tPA, but its brief therapeutic window and complications of treatment constrain its use. One limitation may be its potential to exacerbate impairment of cerebral autoregulation after stroke. Vasodilation is maintained by elevations in cAMP. However, cAMP levels fall after stroke due to over-activation of NMDA receptors (NMDA-Rs) by toxic levels of glutamate, an effect that is exacerbated by tPA. Binding of wild type (wt-) tPA to the low-density lipoprotein-related receptor (LRP) mediates dilation. We propose that binding of wt-tPA to NMDA-Rs reduces cAMP and impairs vasodilation. We hypothesize that tPA-A296-299, a variant that is fibrinolytic but cannot bind to NMDA-Rs, preferentially binds to LRP and increases cAMP and p38, limiting autoregulation impairment after stroke. Methods Stroke was induced by photothrombosis in pigs equipped with a closed cranial window, CBF determined by microspheres, and CSF cAMP and p38 determined by ELISA. Results Stroke decreased CBF. CBF was reduced further during hypotension, indicating impairment of autoregulation. Autoregulation was further impaired by wt-tPA, which was prevented by MK801 and tPA-A296-299. Protection by tPA-A296-299 was blocked by anti-LRP Ab, the LRP antagonist RAP, and the p38 inhibitor SB 203580, but not by control IgG. Stroke reduced CSF cAMP, which was reduced further by wt-tPA, but augmented by tPA-A296-299. CSF p38 was unchanged by wt-tPA, increased by tPA-A296-299, and decreased by anti-LRP Ab and RAP. Conclusions tPA-A296-299 prevents impairment of cerebral autoregulation after stroke through a LRP-dependent increase in cAMP and p38.

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Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

Cited by 58 publications

References 41 publications

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

Identification of a neurovascular signaling pathway regulating seizures in mice

Tissue-Type Plasminogen Activator-A ^296–299 Prevents Impairment of Cerebral Autoregulation After Stroke Through Lipoprotein-Related Receptor–Dependent Increase in cAMP and p38

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Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

Cited by 58 publications

References 41 publications

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

Identification of a neurovascular signaling pathway regulating seizures in mice

Tissue-Type Plasminogen Activator-A 296–299 Prevents Impairment of Cerebral Autoregulation After Stroke Through Lipoprotein-Related Receptor–Dependent Increase in cAMP and p38

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Tissue-Type Plasminogen Activator-A ^296–299 Prevents Impairment of Cerebral Autoregulation After Stroke Through Lipoprotein-Related Receptor–Dependent Increase in cAMP and p38