The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo

Lebeurrier, Nathalie; Liot, Géraldine; López‐Atalaya, José P.; Orset, Cyrille; Fernández‐Monreal, Mónica; Sonderegger, P.; Ali, Carine; Vivien, Denis

doi:10.1016/j.mcn.2005.09.005

Cited by 70 publications

(55 citation statements)

References 31 publications

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“…This region is now known to contain Ͼ10 candidate genes, including tissue plasminogen activator (tPA), an extracellular serine protease, that is used clinically in the treatment of acute occlusive arterial lesions in the brain (9, 10) but carries the risk that it can modify neuronal structure and initiate a proteolytic cascade that ultimately mediates degeneration of neurons after CNS injury (11,12). tPA also can exert other profound and varied neurobiological effects (10,13), some of which can be counteracted by a naturally produced inhibitor, neuroserpin (14,15).…”

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confidence: 99%

Purkinje neuron degeneration in nervous ( nr ) mutant mice is mediated by a metabolic pathway involving excess tissue plasminogen activator

Teng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Purkinje neurons (PNs), the central cells in cerebellar circuitry and function, constitute a vulnerable population in many human genetic, malignant, hypoxic, and toxic diseases. In the nervous (nr) mutant mouse, the majority of PNs die in the fourth to fifth postnatal weeks, but the responsible molecules are unknown. We first disclose a remarkable increase in mRNA expression and protein concentration in the nr cerebellum of tissue plasminogen activator (tPA), a gene closely linked to the mapped but as-yetuncloned nr locus. Evidence that excessive tPA triggers nr PN death was obtained with organotypic slice cultures expressing the nr PN phenotype, in which an inhibitor of tPA led to increased nr PN survival. An antagonist of protein kinase C, a downstream component in the tPA pathway, also increased nr PN survival. Additional downstream targets in the tPA pathway (the mitochondrial voltage-dependent anion channel, brain-derived neurotrophic factor, and neurotrophin 3) were also abnormal, in parallel with the alterations in PN mitochondrial morphology, dendritic growth, and synaptogenesis that culminate in nr PN death and motor incoordination. We thus propose a molecular pathway by which the excessive tPA in nr cerebellum mediates PN degeneration.dendrite development ͉ mitochondria ͉ neurotrophin ͉ synapse ͉ voltage-dependent anion channel

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confidence: 99%

Purkinje neuron degeneration in nervous ( nr ) mutant mice is mediated by a metabolic pathway involving excess tissue plasminogen activator

Teng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…tPA has been shown to aggravate chronic NMDA-induced neuronal excitotoxicity with 24h exposure to low concentration of NMDA (Nicole et al, 2001;Tsirka et al, 1995), and neuroserpin shows the ability to limit the exacerbation of the glutamatergic signaling stimulated by long-term exposure to NMDA (Lebeurrier et al, 2005). However, 2h exposure to an OGD condition also induces an acute excitotoxic injury, where MK-801 protects neurons effi ciently.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, tPA has been indicated to enhance N-methyl-D-aspartic acid (NMDA) receptor-mediated excitatory neuronal death, and tPAdefi cient mice show a dramatic resistance to excitotoxicity (Nicole et al, 2001;Tsirka et al, 1995). Additionally, neuroserpin protects neurons against low concentration NDMA-induced chronic excitotoxicity both in vitro and in vivo (Lebeurrier et al, 2005). A negative correlation between a decrease of serum neuroserpin level and an increase of glutamate has been found in adult ischemic stroke patients recently .…”

Section: Introductionmentioning

confidence: 97%

Effect of neuroserpin in a neonatal hypoxic-ischemic injury model ex vivo

et al. 2012

Biol. Res.

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Hypoxia-ischemia (HI) occurring in immature brains stimulates the expression of tissue-type plasminogen activator (tPA). Neuroserpin is a selected inhibitor of tPA in the central nerves system. However, the role that neuroserpin plays and the possible mechanisms involved during neonatal HI are poorly defi ned. In this study, an oxygen-glucose deprivation and reoxygenation (OGD/R) model was generated with cultured rat cortical neurons mimicking neonatal HI injury ex vivo, and an acute neuronal excitatory injury was induced by exposure to a high concentration of N-methyl-D-aspartic acid (NMDA). Cells received either neuroserpin or MK-801, an antagonist of the NMDA receptor, during OGD/R, and were incubated with or without neuroserpin after NMDA exposure. Cell viability and morphology were detected by a Cell Counting Kit-8 and immunohistochemical staining, respectively. TPA expression and activity were also assessed. We found that MK-801 alleviated injuries induced by OGD/R, suggesting an excitatory damage involvement. Neuroserpin provided a dosedependent neuroprotective eff ect in both OGD/R and acute excitatory injuries by inhibiting the activity of tPA, without aff ecting neuronal tPA expression. Neuroserpin protected neurons against OGD/R even after a delayed administration of 3h. Collectively, our data indicate that neuroserpin protects neurons against OGD/R. mainly by inhibiting tPA-mediated acute neuronal excitotoxicity.

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“…Indeed, neuroserpin protects against cortical damage in mouse models of cerebral infarction. [10][11][12] It can also limit neuronal excitotoxicity and reduce seizures in mouse models of epilepsy 13,14 and affect the toxicity of the Ab peptide that is central to the pathogenesis of Alzheimer's disease. 15,16 Point mutations in the neuroserpin gene underlie the autosomal dominant dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB).…”

Section: Introductionmentioning

confidence: 99%

pH‐dependent stability of neuroserpin is mediated by histidines 119 and 138; Implications for the control of β‐sheet A and polymerization

et al. 2010

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Neuroserpin is a member of the serpin superfamily. Point mutations in the neuroserpin gene underlie the autosomal dominant dementia, familial encephalopathy with neuroserpin inclusion bodies. This is characterized by the retention of ordered polymers of neuroserpin within the endoplasmic reticulum of neurons. pH has been shown to affect the propensity of several serpins to form polymers. In particular, low pH favors the formation of polymers of both a 1 -antitrypsin and antithrombin. We report here opposite effects in neuroserpin, with a striking resistance to polymer formation at acidic pH. Mutation of specific histidine residues showed that this effect is not attributable to the shutter domain histidine as would be predicted by analogy with other serpins. Indeed, mutation of the shutter domain His338 decreased neuroserpin stability but had no effect on the pH dependence of polymerization when compared with the wild-type protein.In contrast, mutation of His119 or His138 reduced the polymerization of neuroserpin at both acidic and neutral pH. These residues are at the lower pole of neuroserpin and provide a novel mechanism to control the opening of b-sheet A and hence polymerization. This mechanism is likely to have evolved to protect neuroserpin from the acidic environment of the secretory granules.

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The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo

Cited by 70 publications

References 31 publications

Purkinje neuron degeneration in nervous ( nr ) mutant mice is mediated by a metabolic pathway involving excess tissue plasminogen activator

Purkinje neuron degeneration in nervous ( nr ) mutant mice is mediated by a metabolic pathway involving excess tissue plasminogen activator

Effect of neuroserpin in a neonatal hypoxic-ischemic injury model ex vivo

pH‐dependent stability of neuroserpin is mediated by histidines 119 and 138; Implications for the control of β‐sheet A and polymerization

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