The Experts below are selected from a list of 837 Experts worldwide ranked by ideXlab platform
Daniel A. Lawrence - One of the best experts on this subject based on the ideXlab platform.
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Linda Fredriksson,
2015Co-Authors: Daniel A. Lawrence, Vicky W. K. Tsang, Nigel P. Birch, Tet Woo Lee, Maria Elena Mir, A Banos, Tsang VwkAbstract:roles of tissue plasminogen activator and its inhibitor Neuroserpin in the nervous system. Front. Cell. Neurosci. 9:396. doi: 10.3389/fncel.2015.00396 Physiological and pathological roles of tissue plasminogen activator and its inhibitor Neuroserpin in the nervous syste
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Neuroserpin polymorphisms and stroke risk in a biracial population: the stroke prevention in young women study
BMC Neurology, 2007Co-Authors: John W. Cole, Daniel A. Lawrence, Manuel Yepes, Adam C. Naj, Jeffrey R. O'connell, O. C. Stine, John D. Sorkin, Marcella A. Wozniak, Barney J. Stern, Laurie J. ReinhartAbstract:Background Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We sought to evaluate the association of Neuroserpin polymorphisms with risk for ischemic stroke among young women.
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Neuroserpin polymorphisms and stroke risk in a biracial population: the stroke prevention in young women study
BMC neurology, 2007Co-Authors: John W. Cole, Daniel A. Lawrence, Manuel Yepes, Adam C. Naj, Jeffrey R. O'connell, O. C. Stine, John D. Sorkin, Marcella A. Wozniak, Barney J. Stern, Laurie J. ReinhartAbstract:Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We sought to evaluate the association of Neuroserpin polymorphisms with risk for ischemic stroke among young women. A population-based case-control study of stroke among women aged 15-49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-matched control subjects (43.1% African-American). Neuroserpin single nucleotide polymorphisms (SNPs) chosen through HapMap were genotyped in the study population and assessed for association with stroke. Of the five SNPs analyzed, the A allele (frequency; Caucasian = 0.56, African-American = 0.42) of SNP rs6797312 located in intron 1 was associated with stroke in an age-adjusted dominant model (AA and AT vs. TT) among Caucasians (OR = 2.05, p = 0.023) but not African-Americans (OR = 0.71, p = 0.387). Models adjusting for other risk factors strengthened the association. Race-specific haplotype analyses, inclusive of SNP rs6797312, again demonstrated significant associations with stroke among Caucasians only. This study provides the first evidence that Neuroserpin is associated with early-onset ischemic stroke among Caucasian women.
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Tissue-type plasminogen activator and Neuroserpin: a well-balanced act in the nervous system?
Trends in Cardiovascular Medicine, 2004Co-Authors: Manuel Yepes, Daniel A. LawrenceAbstract:Tissue-type plasmingen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. tPA is found in the blood, where its primary function is as a thrombolytic enzyme, as well as in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is a fully inhibitory serine proteinase inhibitor (serpin) that reacts preferentially with tPA, and is located in regions of the brain where either tPA message or tPA protein are also found, suggesting that Neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiologic and pathologic events in the CNS, and the role of Neuroserpin as the natural regulator of tPA's activity in these processes.
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Neuroserpin a selective inhibitor of tissue type plasminogen activator in the central nervous system
Thrombosis and Haemostasis, 2004Co-Authors: Manuel Yepes, Daniel A. LawrenceAbstract:Neuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and Neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with Neuroserpin following ischemic stroke or overexpression of the Neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and Neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with Neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human Neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.
Nigel P. Birch - One of the best experts on this subject based on the ideXlab platform.
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Neuroserpin regulates human T cell-T cell interactions and proliferation through inhibition of tissue plasminogen activator.
Journal of Leukocyte Biology, 2019Co-Authors: Evert Jan Loef, Nigel P. Birch, Anna E. S. Brooks, Natalie Lorenz, P. Rod DunbarAbstract:T cells play a key role in mounting an adaptive immune response. T cells are activated upon recognition of cognate Ag presented by an APC. Subsequently, T cells adhere to other activated T cells to form activation clusters, which lead to directed secretion of cytokines between communicating cells. T cell activation clusters have been implicated in regulating activation, proliferation, and memory formation in T cells. We previously reported the expression of the protease inhibitor Neuroserpin by human T cells and showed that expression and intracellular localization is regulated following T cell activation. To gain a better understanding of Neuroserpin in the proteolytic environment postactivation we assessed its role in human T cell clustering and proliferation. Neuroserpin knockdown increased T cell proliferation and cluster formation following T cell activation. This increased cluster formation was dependent on the proteases tissue plasminogen activator (tPA) and plasmin. Furthermore, Neuroserpin knockdown or plasmin treatment of T cells increased the cleavage of annexin A2, a known plasmin target that regulates the actin cytoskeleton. Live cell imaging of activated T cells further indicated a role of the actin cytoskeleton in T cell clustering. The inhibition of actin regulators myosin ATPase and Rho-associated protein kinase signaling completely reversed the Neuroserpin knockdown-induced effects. The results presented in this study reveal a novel role for Neuroserpin and the proteolytic environment in the regulation of T cell activation biology.
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Physiological and pathological functions of Neuroserpin: Regulation of cellular responses through multiple mechanisms
Seminars in Cell & Developmental Biology, 2016Co-Authors: Tet Woo Lee, Vicky W. K. Tsang, Evert Jan Loef, Nigel P. BirchAbstract:Abstract It is 27 years since Neuroserpin was first discovered in the nervous system and identified as a member of the serpin superfamily. Since that time potential roles for this serine protease inhibitor have been identified in neuronal and non-neuronal systems. Many are linked to inhibition of Neuroserpin’s principal enzyme target, tissue plasminogen activator (tPA), although some have been suggested to involve alternate non-inhibitory mechanisms. This review focuses mainly on the inhibitory roles of Neuroserpin and discusses the evidence supporting tPA as the physiological target. While the major sites of Neuroserpin expression are neural, endocrine and immune tissues, most progress on characterizing functional roles for Neuroserpin have been in the brain. Roles in emotional behaviour, synaptic plasticity and neuroprotection in stroke and excitotoxicity models are discussed. Current knowledge on three neurological diseases associated with Neuroserpin mutation or activity, Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB), Alzheimer's disease and brain metastasis is presented. Finally, we consider mechanistic studies that have revealed a distinct inhibitory mechanism for Neuroserpin and its possible implications for Neuroserpin function.
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AAV-Mediated Overexpression of Neuroserpin in the Hippocampus Decreases PSD-95 Expression but Does Not Affect Hippocampal-Dependent Learning and Memory
2016Co-Authors: Vicky W. K. Tsang, Deborah Young, Matthew J. During, Nigel P. BirchAbstract:Neuroserpin is a serine protease inhibitor, or serpin, that is expressed in the nervous system and inhibits the protease tissue plasminogen activator (tPA). Neuroserpin has been suggested to play a role in learning and memory but direct evidence for such a role is lacking. Here we have used an adeno-associated virus (AAV) vector expression system to investigate the effect of Neuroserpin on hippocampal-dependent learning and memory in the young adult rat. A FLAG-tagged Neuroserpin construct was initially characterized by in vitro transcription/translation and transfection into HEK293 cells and shown to interact with tPA and be targeted to the secretory pathway. Targeted injection of a chimeric AAV1/2 vector expressing FLAG-Neuroserpin resulted in localized overexpression in the dorsal hippocampus. Neuroserpin overexpression led to the appearance of an unstable Neuroserpin:tPA complex in zymographic assays consistent with interaction with endogenous tPA in vivo. Rats overexpressing Neuroserpin also showed a significant decrease in the levels of postsynaptic density protein 95, a major postsynaptic scaffolding protein. Three weeks after injection, a range of behavioural tests was performed to measure spatial and associative learning and memory, as well as innate and acquired fear. These tests provided no evidence of a role for Neuroserpin in hippocampal-dependent learning and memory. In summary this study does not support a role for Neuroserpin in hippocampal-dependent learning and memory in young adult rats but does suggest an involvement o
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Neuroserpin Attenuates H2O2-Induced Oxidative Stress in Hippocampal Neurons via AKT and BCL-2 Signaling Pathways.
Journal of Molecular Neuroscience, 2016Co-Authors: Yong Cheng, Y. Peng Loh, Nigel P. BirchAbstract:Oxidative stress plays a critical role in neuronal injury and is associated with various neurological diseases. Here, we explored the potential protective effect of Neuroserpin against oxidative stress in primary cultured hippocampal neurons. Our results show that Neuroserpin inhibits H2O2-induced neurotoxicity in hippocampal cultures as measured by WST, LDH release, and TUNEL assays. We found that Neuroserpin enhanced the activation of AKT in cultures subjected to oxidative stress and that the AKT inhibitor Ly294002 blocked this neuroprotective effect. Neuroserpin increased the expression of the anti-apoptotic protein BCL-2 and blocked the activation of caspase-3. Neuroserpin did not increase the level of neuroprotection over levels seen in neurons transduced with a BCL-2 expression vector, and an inhibitor of Trk receptors, K252a, did not block Neuroserpin’s effect. Taken together, our study demonstrates that Neuroserpin protects against oxidative stress-induced dysfunction and death of primary cultured hippocampal neurons through the AKT-BCL-2 signaling pathway through a mechanism that does not involve the Trk receptors and leads to inhibition of caspase-3 activation.
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Human T cell activation induces synaptic translocation and alters expression of the serine protease inhibitor Neuroserpin and its target protease.
Journal of Leukocyte Biology, 2015Co-Authors: Natalie Lorenz, Evert Jan Loef, Anna E. S. Brooks, P. Rod Dunbar, Daniel Verdon, Chun-jen J. Chen, Claudia Mansell, Catherine E. Angel, Nigel P. BirchAbstract:ABSTRACT Contact between T cells and APCs and activation of aneffective immune response trig ger cellular polarization andthe formation of a structured interface known as theimmunological synapse. Interactions across the synapseand secretion of T cell and APC-derived factors into theperisynaptic compartment regulate synapse formation andactivation of T cells. We report that the serine proteaseinhibitor Neuroserpin, an axonally secreted protein thoughtto play roles in the formation of the neuronal synapse andrefinement of synaptic activity, is expressed in human na ¨iveeffector memory and central memory subsets of CD4 + andCD8 + T cells, as well as monocytes, B cells, and NK cells.Neuroserpin partially colocalized with a TGN38/LFA-1-positive vesicle population in T cells and translocates to theimmunological synapse upon activation with TCR anti-bodies or antigen-pulsed APCs. Activation of T cells trig-gered Neuroserpin secretion, a rapid, 8.4-fold up-regulation of the serine protease tissue plasminogenactivator, the protease target for Neuroserpin, anda delayed, 6.25-fold down-regulation of Neuroserpin ex-pression. Evidence of polarization and regulated neuro-serpin expression was also seen in ex vivo analyses ofhuman lymph nodes and blood-derived T cells. IncreasedNeuroserpin expression was seen in clusters of T cells inthe paracortex of human lymph nodes, with some showingpolarization to areas of cell:cell interaction. Our resultssupport a role for Neuroserpin and tissue plasminogenactivator in activation-controlled proteolytic cleavage ofproteins in the synaptic or perisynaptic space to modulateimmune cell function. J. Leukoc. Biol. 97: 000–000; 2015.
Manuel Yepes - One of the best experts on this subject based on the ideXlab platform.
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Neuroserpin Protects Neurons from Ischemia-Induced Plasmin-Mediated Cell Death Independently of Tissue-Type Plasminogen Activator Inhibition
American Journal of Pathology, 2010Co-Authors: Ramiro Echeverry, Johanna Guzman, Manuel YepesAbstract:The serine proteinase tissue-type plasminogen activator (tPA) and the serine proteinase inhibitor Neuroserpin are both expressed in areas of the brain with the highest vulnerability to hypoxia/ischemia. In vitro studies show that Neuroserpin inhibits tPA and, to a lesser extent, urokinase-type plasminogen activator and plasmin. Experimental middle cerebral artery occlusion (MCAO) increases tPA activity and Neuroserpin expression in ischemic tissue, and genetic deficiency of tPA or either treatment with or overexpression of Neuroserpin decreases the volume of the ischemic lesion following MCAO. These findings have led to the hypothesis that Neuroserpin's neuroprotection is mediated by inhibition of tPA's alleged neurotoxic effect. Ischemic preconditioning is a natural adaptive process whereby exposure to a sublethal insult induces tolerance against a subsequent lethal ischemic injury. Here we demonstrate that exposure to sublethal hypoxia/ischemia increases the Neuroserpin expression in the hippocampal CA1 layer and cerebral cortex, and that Neuroserpin induces ischemic tolerance and decreases the volume of the ischemic lesion following MCAO in wild-type and tPA-deficient (tPA −/− ) neurons and mice. Plasmin induces neuronal death, and this effect is abrogated by either Neuroserpin or the NMDA receptor antagonist MK-801. Neuroserpin also attenuated kainic acid-induced neuronal death. Our data indicate that the neuroprotective effect of Neuroserpin is due to inhibition of plasmin-mediated excitotoxin-induced cell death and is independent of Neuroserpin's ability to inhibit tPA activity.
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Neuroserpin polymorphisms and stroke risk in a biracial population: the stroke prevention in young women study
BMC Neurology, 2007Co-Authors: John W. Cole, Daniel A. Lawrence, Manuel Yepes, Adam C. Naj, Jeffrey R. O'connell, O. C. Stine, John D. Sorkin, Marcella A. Wozniak, Barney J. Stern, Laurie J. ReinhartAbstract:Background Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We sought to evaluate the association of Neuroserpin polymorphisms with risk for ischemic stroke among young women.
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Neuroserpin polymorphisms and stroke risk in a biracial population: the stroke prevention in young women study
BMC neurology, 2007Co-Authors: John W. Cole, Daniel A. Lawrence, Manuel Yepes, Adam C. Naj, Jeffrey R. O'connell, O. C. Stine, John D. Sorkin, Marcella A. Wozniak, Barney J. Stern, Laurie J. ReinhartAbstract:Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We sought to evaluate the association of Neuroserpin polymorphisms with risk for ischemic stroke among young women. A population-based case-control study of stroke among women aged 15-49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-matched control subjects (43.1% African-American). Neuroserpin single nucleotide polymorphisms (SNPs) chosen through HapMap were genotyped in the study population and assessed for association with stroke. Of the five SNPs analyzed, the A allele (frequency; Caucasian = 0.56, African-American = 0.42) of SNP rs6797312 located in intron 1 was associated with stroke in an age-adjusted dominant model (AA and AT vs. TT) among Caucasians (OR = 2.05, p = 0.023) but not African-Americans (OR = 0.71, p = 0.387). Models adjusting for other risk factors strengthened the association. Race-specific haplotype analyses, inclusive of SNP rs6797312, again demonstrated significant associations with stroke among Caucasians only. This study provides the first evidence that Neuroserpin is associated with early-onset ischemic stroke among Caucasian women.
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Tissue-type plasminogen activator and Neuroserpin: a well-balanced act in the nervous system?
Trends in Cardiovascular Medicine, 2004Co-Authors: Manuel Yepes, Daniel A. LawrenceAbstract:Tissue-type plasmingen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. tPA is found in the blood, where its primary function is as a thrombolytic enzyme, as well as in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is a fully inhibitory serine proteinase inhibitor (serpin) that reacts preferentially with tPA, and is located in regions of the brain where either tPA message or tPA protein are also found, suggesting that Neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiologic and pathologic events in the CNS, and the role of Neuroserpin as the natural regulator of tPA's activity in these processes.
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Neuroserpin a selective inhibitor of tissue type plasminogen activator in the central nervous system
Thrombosis and Haemostasis, 2004Co-Authors: Manuel Yepes, Daniel A. LawrenceAbstract:Neuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and Neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with Neuroserpin following ischemic stroke or overexpression of the Neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and Neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with Neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human Neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.
Peter Sonderegger - One of the best experts on this subject based on the ideXlab platform.
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Neuroserpin MUTATION CAUSES ELECTRICAL STATUS EPILEPTICUS OF SLOW-WAVE SLEEP
Neurology, 2008Co-Authors: Marie Coutelier, Peter Sonderegger, Charles Duyckaerts, S. Andries, S. Ghariani, Bernard Dan, K. Van Rijckevorsel, Christian Raftopoulos, Nicolas Deconinck, Francesco ScaravilliAbstract:Conformational diseases result from cellular dysfunctions induced by aberrant aggregation of proteins. They are caused either by excess of secretion of a normal protein, or more frequently, by mutation in a protein, as in prion diseases. Recently, one of them, familial encephalopathy with Neuroserpin inclusion bodies (FENIB, OMIM #604218), an autosomal dominant dementia, was recognized. It is caused by mutations in PI12 (proteinase inhibitor 12, SERPINI1 or Neuroserpin, OMIM #602445), a neuron-specific serine proteinase inhibitor (serpin).1,2 Neuroserpin was first identified in culture medium of chicken axons, then in human neurons.3 It plays roles in synapses and vessel permeability, and is known to be associated with learning, memory, and behavior. It belongs to the serpin super-family, members of which display at least 30% amino acid sequence homology with their archetype, alpha-1-antitrypsin. Mutated Neuroserpin progressively polymerizes in neuronal endoplasmic reticulum, inducing cognitive impairment and sometimes myoclonic epilepsy. Neuropathology is characterized by neuronal intra-cytoplasmic rounded inclusions, homogeneously pale to intensely pink with eosin, and PAS positive after diastase treatment (Collins bodies). Four different mutations have been described in six families affected by FENIB: two in exon 2 (S49P and S52R) and two in exon 9 (H338R and G392E). Known mutations in serpins are localized in the mobile regions of the molecule (exon 2 and 9). They result in proteins …
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Clinical and neuropathologic study of a French family with a mutation in the Neuroserpin gene
Neurology, 2007Co-Authors: Isabelle Gourfinkel-an, Peter Sonderegger, Charles Duyckaerts, Agnès Camuzat, C. Meyrignac, Michel Baulac, Alexis BriceAbstract:Familial encephalopathy with Neuroserpin inclusion bodies is a recently described neurodegenerative disease that is responsible for progressive myoclonic epilepsy or presenile dementia. In a French family with the S52R mutation of the Neuroserpin gene, progressive myoclonic epilepsy was associated with a frontal syndrome. The typical cerebral inclusions (Collins bodies) were abundant in the frontal cortex and in the head of the caudate nucleus but spared the cerebellum.
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Accumulation of mutant Neuroserpin precedes development of clinical symptoms in familial encephalopathy with Neuroserpin inclusion bodies.
American Journal of Pathology, 2007Co-Authors: Giovanna Galliciotti, Serguei Kozlov, Markus Glatzel, Jochen Kinter, Paolo Cinelli, Thomas Rülicke, Peter SondereggerAbstract:Intracellular protein deposition due to aggregation caused by conformational alteration is the hallmark of a number of neurodegenerative disorders, including Parkinson's disease, tauopathies, Huntington's disease, and familial encephalopathy with Neuroserpin inclusion bodies. The latter is an autosomal dominant disorder caused by point mutations in Neuroserpin resulting in its destabilization. Mutant Neuroserpin polymerizes and forms intracellular aggregates that eventually lead to neurodegeneration. We generated genetically modified mice expressing the late-onset S49P-Syracuse or the early-onset S52R-Portland mutation of Neuroserpin in central nervous system neurons. Mice exhibited morphological, biochemical, and clinical features resembling those found in the human disease. Analysis of brains revealed large intraneuronal inclusions composed exclusively of mutant Neuroserpin, accumulating long before the development of clinical symptoms in a time-dependent manner. Clinical symptoms and amount of Neuroserpin inclusions correlated with the predicted instability of the protein. The presence of inclusion bodies in subclinical mice indicates that in humans the prevalence of the disease could be higher than anticipated. In addition to shedding light on the pathophysiology of the human disorder, these mice provide an excellent model to study mechanisms of neurodegeneration or establish novel therapies for familial encephalopathy with Neuroserpin inclusion bodies and other neurodegenerative diseases with intracellular protein deposition.
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Neuroserpin is post-transcriptionally regulated by thyroid hormone.
Brain research. Molecular brain research, 2004Co-Authors: Cristina Navarro-yubero, Peter Sonderegger, Ana Cuadrado, Alberto MuñozAbstract:Neuroserpin is a serine protease inhibitor expressed in the developing and the adult nervous system. Studies with genetically modified mice indicate a role of Neuroserpin in the regulation of anxiety. Mutations in the Neuroserpin gene cause protein polymerization and formation of inclusion bodies leading to progressive myoclonic epilepsy and neurodegeneration. Here we demonstrate that Neuroserpin expression is regulated by thyroid hormone (T3). Neuroserpin RNA levels are down-regulated in cortical layers II/III and VIa, the hippocampus, the retrosplenial cortex and the medial habenular nucleus, but not in cortical layer V or other areas of the hypothyroid rat brain. Concordantly, Neuroserpin RNA and protein expression was induced by T3 in rat PC12 cells containing appropriate thyroid hormone receptor levels. In run-on assays T3 did not affect the transcription rate of the Neuroserpin gene, indicating that regulation was post-transcriptional. Moreover, T3 increased in vitro binding of cytoplasmic proteins to Neuroserpin 3'-UTR RNA and caused biphasic regulation of the stability of this transcript in PC12 cells. Ectopic Neuroserpin expression induced neurite extension in PC12 cells and enhanced neuritogenesis triggered by nerve growth factor. In summary, these results indicate that Neuroserpin expression is post-transcriptionally regulated by T3 at the level of RNA stability.
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Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor Neuroserpin.
Molecular and Cellular Neuroscience, 2003Co-Authors: Rime Madani, Serguei Kozlov, Peter Sonderegger, Jochen Kinter, Paolo Cinelli, Alexander Akhmedov, Hans-peter Lipp, David P. WolferAbstract:Neuroserpin is a neural serpin that inhibits the extracellular protease tissue-type plasminogen activator (tPA). We have generated Neuroserpin-deficient mice which are viable and healthy. Zymographic analysis of Neuroserpin-deficient brain showed unaltered tPA activity, suggesting that other inhibitors contribute to the regulation of tPA and may compensate for the defect. Analysis of explorative behavior revealed selective reduction of locomotor activity in novel environments, an anxiety-like response on the O-maze, and a neophobic response to novel objects. Mice overexpressing Neuroserpin under the control of the Thy1.2 promoter are known to have a reduced brain tPA activity. They showed reduced center exploration in the open-field test and, like Neuroserpin-deficient mice, a neophobic phenotype in the novel object test. Our results implicate Neuroserpin in the regulation of emotional behavior through a mechanism that is at least in part independent of tPA activity. They are the first evidence for a role of protease inhibitors in mood regulation.
David A Lomas - One of the best experts on this subject based on the ideXlab platform.
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Progressive myoclonus epilepsy associated with Neuroserpin inclusion bodies (Neuroserpinosis)
Epileptic Disorders, 2016Co-Authors: Benoit D. Roussel, David A Lomas, Damian C. CrowtherAbstract:Familial encephalopathy with Neuroserpin inclusion bodies (FENIB) is a conformational proteinopathy characterised by neuronal inclusion bodies composed of the serine protease inhibitor (SERPIN), Neuroserpin. Presenting clinically as a familial dementia-epilepsy syndrome, the molecular mechanism of the pathogenic abnormalities in Neuroserpin has been characterised at atomic resolution. There is a remarkable genotype-phenotype correlation between the degree of molecular destabilisation of the several variants of the Neuroserpin protein, their propensity to self-associate and the age of onset of the dementia-epilepsy complex. As with other serpinopathies there appears to be a mix of cell-autonomous toxicity, due to neuronal accumulation of Neuroserpin, and non-cell autonomous toxicity, caused by loss of protease inhibition, in this case the dysregulated protease is likely to be tissue plasminogen activator (tPA). FENIB should be considered in cases of progressive myoclonic epilepsy and dementia particularly where there is family history of neuropsychiatric disease.
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Association between Neuroserpin and molecular markers of brain damage in patients with acute ischemic stroke
Journal of Translational Medicine, 2011Co-Authors: Raquel Rodríguez-gonzález, David A Lomas, Elena Miranda, Mónica Millán, Tomás Sobrino, David Brea, Juan Pérez, Manuel Rodríguez-yáñez, Octavio Moldes, Rogelio LeiraAbstract:Background Neuroserpin has shown neuroprotective effects in animal models of cerebral ischemia and has been associated with functional outcome after ischemic stroke. Our aim was to study whether Neuroserpin serum levels could be associated to biomarkers of excitotoxicity, inflammation and blood brain barrier disruption.
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pH-dependent stability of Neuroserpin is mediated by histidines 119 and 138; Implications for the control of β-sheet A and polymerization
Protein Science, 2009Co-Authors: Didier Belorgey, Peter Hägglöf, Maki Onda, David A LomasAbstract: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 α1-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 β-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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Probing Neuroserpin Polymerization and Interaction with Amyloid-β Peptides Using Single Molecule Fluorescence
Biophysical Journal, 2009Co-Authors: Albert Chiou, David A Lomas, Didier Belorgey, Peter Hägglöf, Angel Orte, Allen Yuyin Chen, Paul Dunne, Susanna Karlsson-li, David KlenermanAbstract:Neuroserpin is a member of the serine proteinase inhibitor superfamily. It can undergo a conformational transition to form polymers that are associated with the dementia familial encephalopathy with Neuroserpin inclusion bodies and the wild-type protein can inhibit the toxicity of amyloid-β peptides in Alzheimer's disease. We have used a single molecule fluorescence method, two color coincidence detection, to determine the rate-limiting steps of the early stages of the polymerization of fluorophore-labeled Neuroserpin and have assessed how this process is altered in the presence of Aβ1–40. Our data show that Neuroserpin polymerization proceeds first by the unimolecular formation of an active monomer, followed by competing processes of both polymerization and formation of a latent monomer from the activated species. These data are not in keeping with the recently proposed domain swap model of polymer formation in which the latent species and activated monomer are likely to be formed by competing pathways directly from the unactivated monomeric serpin. Moreover, the Aβ1–40 peptide forms a weak complex with Neuroserpin (dissociation constant of 10 ± 5 nM) that increases the amount of active monomer thereby increasing the rate of polymerization. The Aβ1–40 is displaced from the complex so that it acts as a catalyst and is not incorporated into Neuroserpin polymers.
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Neuroserpin Polymers Activate NF-κB by a Calcium Signaling Pathway That Is Independent of the Unfolded Protein Response
Journal of Biological Chemistry, 2009Co-Authors: M Davies, Elena Miranda, Benoit D. Roussel, Randal J. Kaufman, Stefan J. Marciniak, David A LomasAbstract:The autosomal dominant dementia familial encephalopathy with Neuroserpin inclusion bodies is characterized by the accumulation of ordered polymers of mutant Neuroserpin within the endoplasmic reticulum of neurones. We show here that intracellular Neuroserpin polymers activate NF-kappaB by a pathway that is independent of the IRE1, ATF6, and PERK limbs of the canonical unfolded protein response but is dependent on intracellular calcium. This pathway provides a mechanism for cells to sense and react to the accumulation of folded structures of mutant serpins within the endoplasmic reticulum. Our results provide strong support for the endoplasmic reticulum overload response being independent of the unfolded protein response.