Journal articles: 'Neuroserpin'

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Galliciotti, Giovanna. "Neuroserpin." Frontiers in Bioscience 11, no. 1 (2006): 33. http://dx.doi.org/10.2741/1778.

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HILL, Rena M., Parmjeet K. PARMAR, Leigh C. COATES, Eva MEZEY, John F. PEARSON, and Nigel P. BIRCH. "Neuroserpin is expressed in the pituitary and adrenal glands and induces the extension of neurite-like processes in AtT-20 cells." Biochemical Journal 345, no. 3 (January 25, 2000): 595–601. http://dx.doi.org/10.1042/bj3450595.

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Two cDNAs encoding the serine protease inhibitor (serpin) neuroserpin were cloned from a rat pituitary cDNA library (rNS-1, 2922 bp; rNS-2, 1599 bp). In situ hybridization histochemistry showed neuroserpin transcripts in the intermediate, anterior and posterior lobes of the pituitary gland and medullary cells in the adrenal gland. Expression of rNS-1 mRNA was restricted to selected cells in the pituitary gland. Analysis of purified secretory-granule fractions from pituitary and adrenal tissues indicated that neuroserpin was found in dense-cored secretory granules. This result suggested that endocrine neuroserpin may regulate intragranular proteases or inhibit enzymes following regulated secretion. To investigate the function of neuroserpin in endocrine tissues we established stable anterior pituitary AtT-20 cell lines expressing neuroserpin. Cells with increased levels of neuroserpin responded by extending neurite-like processes. Extracellular proteolysis by serine protease plasminogen activators has been suggested to regulate neurite outgrowth. As neuroserpin inhibits tissue plasminogen activator (tPA) in vitro, we measured plasminogen-activator levels. Zymographic analysis indicated that AtT-20 cells synthesized and secreted a plasminogen activator identical in size to tPA. A higher-molecular-mass tPA-neuroserpin complex was also observed in AtT-20-cell conditioned culture medium. tPA levels were similar in parent AtT-20 cells and a stable cell line with increased levels of neuroserpin. There was no accumulation of a tPA-neuroserpin complex. Together these results identify endocrine cells as an important source of neuroserpin. Moreover they suggest that neuroserpin is released from dense-cored secretory granules to regulate cell-extracellular matrix interactions through a mechanism that may not directly involve tPA.

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Çinar, Rugül Köse. "Neuroserpin in Bipolar Disorder." Current Topics in Medicinal Chemistry 20, no. 7 (April 23, 2020): 518–23. http://dx.doi.org/10.2174/1568026620666200131125526.

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Objective: Neuroserpin is a serine protease inhibitor predominantly expressed in the nervous system functioning mainly in neuronal migration and axonal growth. Neuroprotective effects of neuroserpin were shown in animal models of stroke, brain, and spinal cord injury. Postmortem studies confirmed the involvement of neuroserpin in Alzheimer’s disease. Since altered adult neurogenesis was postulated as an aetiological mechanism for bipolar disorder, the possible effect of neuroserpin gene expression in the disorder was evaluated. Methods: Neuroserpin mRNA expression levels were examined in the peripheral blood of bipolar disorder type I manic and euthymic patients and healthy controls using the polymerase chain reaction method. The sample comprised of 60 physically healthy, middle-aged men as participants who had no substance use disorder. Results: The gene expression levels of neuroserpin were found lower in the bipolar disorder patients than the healthy controls (p=0.000). The neuroserpin levels did not differ between mania and euthymia (both 96% down-regulated compared to the controls). Conclusion: Since we detected differences between the patients and the controls, not the disease states, the dysregulation in the neuroserpin gene could be interpreted as a result of the disease itself.

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Kennedy, Sarah, Angela van Diepen, Cecilia van den Hurk, Leigh Coates, Tet Woo Lee, Lena Ostrovsky, Elena Miranda, et al. "Expression of the serine protease inhibitor neuroserpin in cells of the human myeloid lineage." Thrombosis and Haemostasis 97, no. 03 (2007): 394–99. http://dx.doi.org/10.1160/th06-09-0543.

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SummaryMyeloid progenitors in the bone marrow differentiate into most of the major cell types of the immune system, including macrophages and dendritic cells. These cells play important roles in both innate and adaptive immunity. They express a number of proteases and protease inhibitors including members of the serine proteinase inhibitor or serpin superfamily. In this study we report the differential expression of neuroserpin in cells of the human myeloid lineage. Neuroserpin was highly expressed and secreted following the differentiation of monocytes to macrophages and dendritic cells. Activation of dendritic cells with lipopolysaccharide resulted in increased neuroserpin mRNA levels but no neuroserpin secretion. Confocal immunofluorescence microscopy showed neuroserpin was differentially localised in human myeloid cells. In macrophages and dendritic cells it was concentrated in vesicles located in close proximity to the plasma membrane. The majority of activated dendritic cells also exhibited an intracellular focal concentration of neuroserpin which co-localised with the lysosomal/late endosomal marker LAMP-1. As neuroserpin inhibits tissue plasminogen activator, a comparative analysis of tPA and plasminogen activator inhibitor-1 (PAI-I) expression was undertaken. This analysis revealed differential expression of PAI-I and neuroserpin suggesting they may have different functions in human immune cells.

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Sobrino, Tomás, Elena Miranda, David Brea, Natalia Pérez de la Ossa, Miguel Blanco, Juan Pérez, Laura Dorado, et al. "The natural tissue plasminogen activator inhibitor neuroserpin and acute ischaemic stroke outcome." Thrombosis and Haemostasis 105, no. 03 (2011): 421–29. http://dx.doi.org/10.1160/th10-09-0621.

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SummaryNeuroserpin is a brain-derived natural inhibitor of tissue plasminogen activator (tPA) that has shown neuroprotective effects in animal models of brain ischaemia. Our aim was to investigate the association of neuroserpin levels in blood with functional outcome in patients with acute ischaemic stroke. Due to the potential effect of tPA treatment interfering on neuroserpin levels, we studied two different cohorts: 129 patients not treated with tPA and 80 patients treated with intravenous tPA within 3 hours (h) from symptoms onset. Neuroserpin levels were measured by ELISA. Good functional outcome at three months was defined as Rankin scale score ≤2. In the two cohorts, serum neuroserpin levels on admission were significantly higher than at 24 h, 72 h and in healthy subjects. In non tPA-treated patients, neuroserpin levels decrease at 24 h, but not levels at baseline, were associated with good outcome (for each quartile decrease, adjusted odds ratio [OR] 15.0; 95% confidence interval [CI], 3.5 to 66). In the tPA-treated cohort, high neuroserpin levels before tPA bolus had the stronger effect on favourable outcome (for each quartile, OR 13.5; 95%CI, 3.9 to 47). Furthermore, for each quartile in neuroserpin levels before tPA bolus there was a 80% (95%CI, 48 to 92) reduction in the probability of subsequent parenchymal haematoma. In summary, high serum neuroserpin levels before intravenous tPA and neuroserpin levels decrease at 24 h after ischaemic stroke, independently of tPA treatment, are associated with good functional outcome. These findings support the concept that neuroserpin might play an important role during cerebral ischaemia.

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de Groot, Dorien M., and Gerard J. M. Martens. "Expression of Neuroserpin Is Linked to Neuroendocrine Cell Activation." Endocrinology 146, no. 9 (September 1, 2005): 3791–99. http://dx.doi.org/10.1210/en.2005-0108.

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Abstract Inhibitors of serine proteases (serpins) are important regulators of intracellular and extracellular proteolytic pathways, and they function by forming an irreversible complex with their substrate. Neuroserpin represents a neuroendocrine-specific serpin family member that is expressed in brain regions displaying synaptic plasticity. In this study, we explored the biosynthesis of endogenous neuroserpin in a neuroendocrine model system, namely the melanotrope cells of Xenopus intermediate pituitary. The biosynthetic activity of these cells can be physiologically manipulated (high and low production of the prohormone proopiomelanocortin in black and white animals, respectively), resulting from a synaptic plasticity in innervating hypothalamic neurons. We found that neuroserpin was also differentially expressed in the Xenopus intermediate, but not anterior, pituitary with a 3-fold higher mRNA and more than 30-fold higher protein expression in the active vs. the inactive melanotrope cells. Two newly synthesized glycosylated forms of the neuroserpin protein (47 and 50 kDa) were produced and secreted by the active cells. Intriguingly, neuroserpin was found in an approximately 130-kDa sodium dodecyl sulfate-stable complex in the active, but not in the inactive, melanotrope cells, which correlated with the high and low proopiomelanocortin expression levels, respectively. In conclusion, we report on the biosynthesis of neuroserpin in a physiological context, and we find that the induction of neuroserpin expression and the formation of the 130-kDa neuroserpin-containing complex are linked to neuroendocrine cell activation.

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Yepes, Manuel, Maria Sandkvist, Mike K. K. Wong, Timothy A. Coleman, Elizabeth Smith, Stanley L. Cohan, and Daniel A. Lawrence. "Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis." Blood 96, no. 2 (July 15, 2000): 569–76. http://dx.doi.org/10.1182/blood.v96.2.569.

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Abstract Neuroserpin, a recently identified inhibitor of tissue-type plasminogen activator (tPA), is primarily localized to neurons within the central nervous system, where it is thought to regulate tPA activity. In the present study neuroserpin expression and its potential therapeutic benefits were examined in a rat model of stroke. Neuroserpin expression increased in neurons surrounding the ischemic core (ischemic penumbra) within 6 hours of occlusion of the middle cerebral artery and remained elevated during the first week after the ischemic insult. Injection of neuroserpin directly into the brain immediately after infarct reduced stroke volume by 64% at 72 hours compared with control animals. In untreated animals both tPA and urokinase-type plasminogen activator (uPA) activity was significantly increased within the region of infarct by 6 hours after reperfusion. Activity of tPA then decreased to control levels by 72 hours, whereas uPA activity continued to rise and was dramatically increased by 72 hours. Both tPA and uPA activity were significantly reduced in neuroserpin-treated animals. Immunohistochemical staining of basement membrane laminin with a monoclonal antibody directed toward a cryptic epitope suggested that proteolysis of the basement membrane occurred as early as 10 minutes after reperfusion and that intracerebral administration of neuroserpin significantly reduced this proteolysis. Neuroserpin also decreased apoptotic cell counts in the ischemic penumbra by more than 50%. Thus, neuroserpin may be a naturally occurring neuroprotective proteinase inhibitor, whose therapeutic administration decreases stroke volume most likely by inhibiting proteinase activity and subsequent apoptosis associated with focal cerebral ischemia/reperfusion.

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Yepes, Manuel, Maria Sandkvist, Mike K. K. Wong, Timothy A. Coleman, Elizabeth Smith, Stanley L. Cohan, and Daniel A. Lawrence. "Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis." Blood 96, no. 2 (July 15, 2000): 569–76. http://dx.doi.org/10.1182/blood.v96.2.569.014k35_569_576.

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Neuroserpin, a recently identified inhibitor of tissue-type plasminogen activator (tPA), is primarily localized to neurons within the central nervous system, where it is thought to regulate tPA activity. In the present study neuroserpin expression and its potential therapeutic benefits were examined in a rat model of stroke. Neuroserpin expression increased in neurons surrounding the ischemic core (ischemic penumbra) within 6 hours of occlusion of the middle cerebral artery and remained elevated during the first week after the ischemic insult. Injection of neuroserpin directly into the brain immediately after infarct reduced stroke volume by 64% at 72 hours compared with control animals. In untreated animals both tPA and urokinase-type plasminogen activator (uPA) activity was significantly increased within the region of infarct by 6 hours after reperfusion. Activity of tPA then decreased to control levels by 72 hours, whereas uPA activity continued to rise and was dramatically increased by 72 hours. Both tPA and uPA activity were significantly reduced in neuroserpin-treated animals. Immunohistochemical staining of basement membrane laminin with a monoclonal antibody directed toward a cryptic epitope suggested that proteolysis of the basement membrane occurred as early as 10 minutes after reperfusion and that intracerebral administration of neuroserpin significantly reduced this proteolysis. Neuroserpin also decreased apoptotic cell counts in the ischemic penumbra by more than 50%. Thus, neuroserpin may be a naturally occurring neuroprotective proteinase inhibitor, whose therapeutic administration decreases stroke volume most likely by inhibiting proteinase activity and subsequent apoptosis associated with focal cerebral ischemia/reperfusion.

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Yepes, Manuel, and Daniel Lawrence. "Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system." Thrombosis and Haemostasis 91, no. 03 (2004): 457–64. http://dx.doi.org/10.1160/th03-12-0766.

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SummaryNeuroserpin 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.

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Vezzani, Annamaria. "Tissue Plasminogen Activator, Neuroserpin, and Seizures." Epilepsy Currents 5, no. 4 (July 2005): 130–32. http://dx.doi.org/10.1111/j.1535-7511.2005.00041.x.

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Ethanol-withdrawal Seizures Are Controlled by Tissue Plasminogen Activator via Modulation of NR2B-containing NMDA Receptors Pawlak R, Melchor JP, Matys T, Skrzypiec AE, Strickland S Proc Natl Acad Sci USA 2005;102:443–448 Chronic ethanol abuse causes upregulation of N-methyl-D-aspartate (NMDA) receptors, which underlies seizures and brain damage on ethanol withdrawal (EW). Here we show that tissue plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with upregulation of NMDA receptors. tPA interacts with NR2B-containing NMDA receptors and is required for upregulation of the NR2B subunit in response to ethanol. As a consequence, tPA-deficient mice have reduced NR2B, extracellular signal-regulated kinase 1/2 phosphorylation, and seizures after EW. tPA-mediated facilitation of EW seizures is abolished by NR2B-specific NMDA antagonist ifenprodil. These results indicate that tPA mediates the development of physical dependence on ethanol by regulating NR2B-containing NMDA receptors. Neuroserpin Portland (Ser52Arg) Is Trapped as an Inactive Intermediate That Rapidly Forms Polymers: Implications for the Epilepsy Seen in the Dementia FENIB Belorgey D, Sharp LK, Crowther DC, Onda M, Johansson J, Lomas DA Eur J Biochem 2004;271:3360–3367 The dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), is caused by point mutations in the neuroserpin gene. We have shown a correlation between the predicted effect of the mutation and the number of intracerebral inclusions, and an inverse relation with the age at onset of disease. Our previous work has shown that the intraneuronal inclusions in FENIB result from the sequential interaction between the reactive center loop of one neuroserpin molecule with β-sheet A of the next. We show here that neuroserpin Portland (Ser52Arg), which causes a severe form of FENIB, also forms loop-sheet polymers but at a faster rate, in keeping with the more severe clinical phenotype. The Portland mutant has a normal unfolding transition in urea and a normal melting temperature but is inactive as a proteinase inhibitor. This results in part from the reactive loop being in a less accessible conformation to bind to the target enzyme, tissue plasminogen activator. These results, with those of the CD analysis, are in keeping with the reactive center loop of neuroserpin Portland being partially inserted into β-sheet A to adopt a conformation similar to an intermediate on the polymerization pathway. Our data provide an explanation for the number of inclusions and the severity of dementia in FENIB associated with neuroserpin Portland. Moreover, the inactivity of the mutant may result in uncontrolled activity of tissue plasminogen activator, and so explain the epileptic seizures seen in individuals with more severe forms of the disease.

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Kulla, Andres, Aadu Simisker, Vappu Sirén, Daniel Lawrence, Toomas Asser, Antti Vaheri, and Tambet Teesalu. "Tissue plasminogen activator and neuroserpin are widely expressed in the human central nervous system." Thrombosis and Haemostasis 92, no. 08 (2004): 358–68. http://dx.doi.org/10.1160/th02-12-0310.

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SummaryTissue plasminogen activator (tPA) is increasingly recognized to play important roles in various physiological and pathological processes in the central nervous system (CNS). Much of the data on the involvement of plasminogen activators in neurophysiology and -pathology have been derived from studies on experimental animals. We have now performed a systematic characterization of the expression of tPA and its inhibitor, neuroserpin, in normal human CNS. Brain and spinal cord samples from 30-36 anatomic locations covering all major brain regions were collected at 9 autopsies of donors with no neurological disease. Tissues were embedded in paraffin and tissue arrays were constructed. In two cases parallel samples were snap-frozen for biochemical analysis. Expression and activity profiling of tPA and neuroserpin were performed by immunohistochemistry, in situ hybridization, immunocapture and zymography assays. In the adult CNS, tPA was expressed at the mRNA and protein levels in many types of neurons, in particular in thalamus, cortex of cerebellum, pontine nuclei, neocortex, limbic system, and medulla oblongata. Interestingly, tPA was often co-expressed with its CNS inhibitor, neuroserpin. Despite overlapping expression of tPA and neuroserpin, zymography and immunocapture assays demonstrated that human neural tissue is a rich source of active tPA. Our analysis documents a detailed map of expression of tPA and its inhibitor in the human CNS and is compatible with the view that tPA is a key player in CNS physiology and pathology.

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Onda, Maki, Didier Belorgey, Lynda K. Sharp, and David A. Lomas. "Latent S49P Neuroserpin Forms Polymers in the Dementia Familial Encephalopathy with Neuroserpin Inclusion Bodies." Journal of Biological Chemistry 280, no. 14 (January 21, 2005): 13735–41. http://dx.doi.org/10.1074/jbc.m413282200.

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Takao, Masaki, Merrill D. Benson, Jill R. Murrell, Masahide Yazaki, Pedro Piccardo, Frederick W. Unverzagt, Richard L. Davis, et al. "Neuroserpin Mutation S52R Causes Neuroserpin Accumulation in Neurons and Is Associated with Progressive Myoclonus Epilepsy." Journal of Neuropathology & Experimental Neurology 59, no. 12 (December 2000): 1070–86. http://dx.doi.org/10.1093/jnen/59.12.1070.

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Noto, Rosina, Maria Grazia Santangelo, Stefano Ricagno, Maria Rosalia Mangione, Matteo Levantino, Margherita Pezzullo, Vincenzo Martorana, Antonio Cupane, Martino Bolognesi, and Mauro Manno. "The Tempered Polymerization of Human Neuroserpin." PLoS ONE 7, no. 3 (March 6, 2012): e32444. http://dx.doi.org/10.1371/journal.pone.0032444.

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Davis, Richard L., Peter D. Holohan, Antony E. Shrimpton, Arthur H. Tatum, John Daucher, George H. Collins, Robert Todd, et al. "Familial Encephalopathy with Neuroserpin Inclusion Bodies." American Journal of Pathology 155, no. 6 (December 1999): 1901–13. http://dx.doi.org/10.1016/s0002-9440(10)65510-1.

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Miranda, E., and D. A. Lomas. "Neuroserpin: a serpin to think about." Cellular and Molecular Life Sciences 63, no. 6 (February 7, 2006): 709–22. http://dx.doi.org/10.1007/s00018-005-5077-4.

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Takehara, Sayaka, Juan Zhang, Xiaoyan Yang, Nobuyuki Takahashi, Bunzo Mikami, and Maki Onda. "Refolding and Polymerization Pathways of Neuroserpin." Journal of Molecular Biology 403, no. 5 (November 2010): 751–62. http://dx.doi.org/10.1016/j.jmb.2010.07.047.

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Galliciotti, Giovanna, Markus Glatzel, Jochen Kinter, Serguei V. Kozlov, Paolo Cinelli, Thomas Rülicke, and Peter Sonderegger. "Accumulation of Mutant Neuroserpin Precedes Development of Clinical Symptoms in Familial Encephalopathy with Neuroserpin Inclusion Bodies." American Journal of Pathology 170, no. 4 (April 2007): 1305–13. http://dx.doi.org/10.2353/ajpath.2007.060910.

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Caccia, Sonia, Stefano Ricagno, and Martino Bolognesi. "Molecular bases of neuroserpin function and pathology." BioMolecular Concepts 1, no. 2 (August 1, 2010): 117–30. http://dx.doi.org/10.1515/bmc.2010.019.

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AbstractSerpins build a large and evolutionary widespread protein superfamily, hosting members that are mainly Ser-protease inhibitors. Typically, serpins display a conserved core domain composed of three main β-sheets and 9–10 α-helices, for a total of approximately 350 amino acids. Neuroserpin (NS) is mostly expressed in neurons and in the central and peripheral nervous systems, where it targets tissue-type plasminogen activator. NS activity is relevant for axogenesis, synaptogenesis and synaptic plasticity. Five (single amino acid) NS mutations are associated with severe neurodegenerative disease in man, leading to early onset dementia, epilepsy and neuronal death. The functional aspects of NS protease inhibition are linked to the presence of a long exposed loop (reactive center loop, RCL) that acts as bait for the incoming partner protease. Large NS conformational changes, associated with the cleavage of the RCL, trap the protease in an acyl-enzyme complex. Contrary to other serpins, this complex has a half-life of approximately 10 min. Conformational flexibility is held to be at the bases of NS polymerization leading to Collins bodies intracellular deposition and neuronal damage in the pathological NS variants. Two main general mechanisms of serpin polymerization are currently discussed. Both models require the swapping of the RCL among neighboring serpin molecules. Specific differences in the size of swapped regions, as well as differences in the folding stage at which polymerization can occur, distinguish the two models. The results provided by recent crystallographic and biophysical studies allow rationalization of the functional and pathological roles played by NS based on the analysis of four three-dimensional structures.

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Benvenga, Salvatore. "Conformational mutations in neuroserpin and familial dementias." Lancet 360, no. 9346 (November 2002): 1696. http://dx.doi.org/10.1016/s0140-6736(02)11626-6.

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Visentin, Cristina, Luca Broggini, Benedetta Maria Sala, Rosaria Russo, Alberto Barbiroli, Carlo Santambrogio, Simona Nonnis, et al. "Glycosylation Tunes Neuroserpin Physiological and Pathological Properties." International Journal of Molecular Sciences 21, no. 9 (May 3, 2020): 3235. http://dx.doi.org/10.3390/ijms21093235.

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Neuroserpin (NS) is a member of the serine protease inhibitors superfamily. Specific point mutations are responsible for its accumulation in the endoplasmic reticulum of neurons that leads to a pathological condition named familial encephalopathy with neuroserpin inclusion bodies (FENIB). Wild-type NS presents two N-glycosylation chains and does not form polymers in vivo, while non-glycosylated NS causes aberrant polymer accumulation in cell models. To date, all in vitro studies have been conducted on bacterially expressed NS, de facto neglecting the role of glycosylation in the biochemical properties of NS. Here, we report the expression and purification of human glycosylated NS (gNS) using a novel eukaryotic expression system, LEXSY. Our results confirm the correct N-glycosylation of wild-type gNS. The fold and stability of gNS are not altered compared to bacterially expressed NS, as demonstrated by the circular dichroism and intrinsic tryptophan fluorescence assays. Intriguingly, gNS displays a remarkably reduced polymerisation propensity compared to non-glycosylated NS, in keeping with what was previously observed for wild-type NS in vivo and in cell models. Thus, our results support the relevance of gNS as a new in vitro tool to study the molecular bases of FENIB.

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Davis, R. L., A. H. Tutum, A. E. Shrimpton, and P. D. Holohan. "FAMILIAL ENCEPHALOPATHY WITH NEUROSERPIN INCLUSION BODIES (FENIB)." Journal of Neuropathology and Experimental Neurology 58, no. 5 (May 1999): 514. http://dx.doi.org/10.1097/00005072-199905000-00033.

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Ricagno, Stefano, Sonia Caccia, Graziella Sorrentino, Giovanni Antonini, and Martino Bolognesi. "Human Neuroserpin: Structure and Time-Dependent Inhibition." Journal of Molecular Biology 388, no. 1 (April 2009): 109–21. http://dx.doi.org/10.1016/j.jmb.2009.02.056.

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Osterwalder, T., J. Contartese, E. T. Stoeckli, T. B. Kuhn, and P. Sonderegger. "Neuroserpin, an axonally secreted serine protease inhibitor." EMBO Journal 15, no. 12 (June 1996): 2944–53. http://dx.doi.org/10.1002/j.1460-2075.1996.tb00657.x.

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Vapore, Valentina, Corrado Mazzaglia, Diego Sibilia, Mara Del Vecchio, Gernot Fruhmann, Marta Valenti, Elena Miranda, Teresa Rinaldi, Joris Winderickx, and Cristina Mazzoni. "Neuroserpin Inclusion Bodies in a FENIB Yeast Model." Microorganisms 9, no. 7 (July 13, 2021): 1498. http://dx.doi.org/10.3390/microorganisms9071498.

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FENIB (familial encephalopathy with neuroserpin inclusion bodies) is a human monogenic disease caused by point mutations in the SERPINI1 gene, characterized by the intracellular deposition of polymers of neuroserpin (NS), which leads to proteotoxicity and cell death. Despite the different cell and animal models developed thus far, the exact mechanism of cell toxicity elicited by NS polymers remains unclear. Here, we report that human wild-type NS and the polymerogenic variant G392E NS form protein aggregates mainly localized within the endoplasmic reticulum (ER) when expressed in the yeast S. cerevisiae. The expression of NS in yeast delayed the exit from the lag phase, suggesting that NS inclusions cause cellular stress. The cells also showed a higher resistance following mild oxidative stress treatments when compared to control cells. Furthermore, the expression of NS in a pro-apoptotic mutant strain-induced cell death during aging. Overall, these data recapitulate phenotypes observed in mammalian cells, thereby validating S. cerevisiae as a model for FENIB.

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Chen, Hao, Donghang Zheng, Jeff Abbott, Liying Liu, Mee Y. Bartee, Maureen Long, Jennifer Davids, et al. "Myxomavirus-Derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection." Antimicrobial Agents and Chemotherapy 57, no. 9 (June 17, 2013): 4114–27. http://dx.doi.org/10.1128/aac.02594-12.

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ABSTRACTLethal viral infections produce widespread inflammation with vascular leak, clotting, and bleeding (disseminated intravascular coagulation [DIC]), organ failure, and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by an inflammatory cytokine storm and also can induce systemic inflammation with loss of normalserineproteaseinhibitor (serpin) regulation. Myxomavirus secretes a potent anti-inflammatory serpin, Serp-1, that inhibits clotting factor X (fX) and thrombolytic tissue- and urokinase-type plasminogen activators (tPA and uPA) with anti-inflammatory activity in multiple animal models. Purified serpin significantly improved survival in a murine gammaherpesvirus 68 (MHV68) infection in gamma interferon receptor (IFN-γR) knockout mice, a model for lethal inflammatory vasculitis. Treatment of MHV68-infected mice with neuroserpin, a mammalian serpin that inhibits only tPA and uPA, was ineffective. Serp-1 reduced virus load, lung hemorrhage, and aortic, lung, and colon inflammation in MHV68-infected mice and also reduced virus load. Neuroserpin suppressed a wide range of immune spleen cell responses after MHV68 infection, while Serp-1 selectively increased CD11c+splenocytes (macrophage and dendritic cells) and reduced CD11b+tissue macrophages. Serp-1 altered gene expression for coagulation and inflammatory responses, whereas neuroserpin did not. Serp-1 treatment was assessed in a second viral infection, mouse-adapted Zaire ebolavirus in wild-type BALB/c mice, with improved survival and reduced tissue necrosis. In summary, treatment with this unique myxomavirus-derived serpin suppresses systemic serine protease and innate immune responses caused by unrelated lethal viral infections (both RNA and DNA viruses), providing a potential new therapeutic approach for treatment of lethal viral sepsis.

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Schipanski, Angela, Felix Oberhauser, Melanie Neumann, Sascha Lange, Beata Szalay, Susanne Krasemann, Fred W. van Leeuwen, Giovanna Galliciotti, and Markus Glatzel. "The lectin OS-9 delivers mutant neuroserpin to endoplasmic reticulum associated degradation in familial encephalopathy with neuroserpin inclusion bodies." Neurobiology of Aging 35, no. 10 (October 2014): 2394–403. http://dx.doi.org/10.1016/j.neurobiolaging.2014.04.002.

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Man, Heng‐Ye, and Xin‐Ming Ma. "A role for neuroserpin in neuron morphological development." Journal of Neurochemistry 121, no. 4 (April 12, 2012): 495–96. http://dx.doi.org/10.1111/j.1471-4159.2012.07655.x.

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Navarro-Yubero, Cristina, Ana Cuadrado, Peter Sonderegger, and Alberto Muñoz. "Neuroserpin is post-transcriptionally regulated by thyroid hormone." Molecular Brain Research 123, no. 1-2 (April 2004): 56–65. http://dx.doi.org/10.1016/j.molbrainres.2003.12.018.

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Davis, Richard L., Antony E. Shrimpton, Peter D. Holohan, Charles Bradshaw, David Feiglin, George H. Collins, Peter Sonderegger, et al. "Familial dementia caused by polymerization of mutant neuroserpin." Nature 401, no. 6751 (September 1999): 376–79. http://dx.doi.org/10.1038/43894.

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Santangelo, Maria Grazia, Rosina Noto, Matteo Levantino, Antonio Cupane, Stefano Ricagno, Margherita Pezzullo, Martino Bolognesi, Maria Rosalia Mangione, Vincenzo Martorana, and Mauro Manno. "On the molecular structure of human neuroserpin polymers." Proteins: Structure, Function, and Bioinformatics 80, no. 1 (November 9, 2011): 8–13. http://dx.doi.org/10.1002/prot.23197.

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Cinelli, Paolo, Rime Madani, Nobusuke Tsuzuki, Philippe Vallet, Margarete Arras, Chunnian N. Zhao, Thomas Osterwalder, Thomas Rülicke, and Peter Sonderegger. "Neuroserpin, a Neuroprotective Factor in Focal Ischemic Stroke." Molecular and Cellular Neuroscience 18, no. 5 (November 2001): 443–57. http://dx.doi.org/10.1006/mcne.2001.1028.

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33

Ekeowa, Ugo I., Bibek Gooptu, Didier Belorgey, Peter Hägglöf, Susanna Karlsson-Li, Elena Miranda, Juan Pérez, et al. "α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies." Clinical Science 116, no. 12 (May 14, 2009): 837–50. http://dx.doi.org/10.1042/cs20080484.

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α1-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes α1-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant α1-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (α1-antitrypsin and α1-antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of α1-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.

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Ishigami, Shoji, Maria Sandkvist, Foon Tsui, Elizabeth Moore, Timothy A. Coleman, and Daniel A. Lawrence. "Identification of a novel targeting sequence for regulated secretion in the serine protease inhibitor neuroserpin." Biochemical Journal 402, no. 1 (January 25, 2007): 25–34. http://dx.doi.org/10.1042/bj20061170.

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Ns (neuroserpin) is a member of the serpin (serine protease inhibitor) gene family that is primarily expressed within the central nervous system. Its principal target protease is tPA (tissue plasminogen activator), which is thought to contribute to synaptic plasticity and to be secreted in a stimulus-dependent manner. In the present study, we demonstrate in primary neuronal cultures that Ns co-localizes in LDCVs (large dense core vesicles) with the regulated secretory protein chromogranin B. We also show that Ns secretion is regulated and can be specifically induced 4-fold by secretagogue treatment. A novel 13-amino-acid sorting signal located at the C-terminus of Ns is identified that is both necessary and sufficient to target Ns to the regulated secretion pathway. Its deletion renders Ns no longer responsive to secretagogue stimulation, whereas PAI-Ns [Ns (neuroserpin)–PAI-1 (plasminogen activator inhibitor-1) chimaera appending the last 13 residues of Ns sequence to the C-terminus of PAI-1] shifts PAI-1 secretion into a regulated secretory pathway.

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35

Visentin, Cristina, Loana Musso, Luca Broggini, Francesca Bonato, Rosaria Russo, Claudia Moriconi, Martino Bolognesi, et al. "Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors." Life 10, no. 7 (July 11, 2020): 111. http://dx.doi.org/10.3390/life10070111.

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Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic reticulum of neurons in the central nervous system. To date, embelin (EMB) is the only known inhibitor of NS polymerization in vitro. This molecule is capable of preventing NS polymerization and dissolving preformed polymers. Here, we show that lowering EMB concentration results in increasing size of NS oligomers in vitro. Moreover, we observe that in cells expressing NS, the polymerization of G392E NS is reduced, but this effect is mediated by an increased proteasomal degradation rather than polymerization impairment. For these reasons we designed a systematic chemical evolution of the EMB scaffold aimed to improve its anti-polymerization properties. The effect of EMB analogs against NS polymerization was assessed in vitro. None of the EMB analogs displayed an anti-polymerization activity better than the one reported for EMB, indicating that the EMB–NS interaction surface is very specific and highly optimized. Thus, our results indicate that EMB is, to date, still the best candidate for developing a treatment against NS polymerization.

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36

Lomas, D. A., A. Lourbakos, S. A. Cumming, and D. Belorgey. "Hypersensitive mousetraps, α1-antitrypsin deficiency and dementia." Biochemical Society Transactions 30, no. 2 (April 1, 2002): 89–92. http://dx.doi.org/10.1042/bst0300089.

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α1-Antitrypsin functions as a ‘mousetrap’ to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu342 → Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and β-sheet A of another. These loop-sheet polymers accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z α1-antitrypsin homozygote to emphysema. Loop-sheet polymerization is now recognized to underlie deficiency variants of other members of the serine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and α1-anti-chymotrypsin, which are associated with thrombosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin inclusion bodies. Our understanding of the structural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must now be achieved in vivo if we are to treat the associated clinical syndromes.

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37

Roussel, Benoit D., David A. Lomas, and Damian C. Crowther. "Progressive myoclonus epilepsy associated with neuroserpin inclusion bodies (neuroserpinosis)." Epileptic Disorders 18, S2 (September 2016): 103–10. http://dx.doi.org/10.1684/epd.2016.0847.

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38

Godfraind, Catherine, Marie Coutelier, Sibille Andries, Germaine van Rijckevorsel, Francesco Scaravilli, and Miikka Vikkula. "The first de novo mutation in the neuroserpin gene." Journal of Neuropathology and Experimental Neurology 66, no. 5 (May 2007): 430–31. http://dx.doi.org/10.1097/01.jnen.0000268854.67043.f1.

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39

Lebeurrier, Nathalie, Géraldine Liot, Jose-Pascual Lopez-Atalaya, Monica Fernandez-Monreal, Peter Sonderegger, Denis Vivien, and Carine Ali. "Neuroprotective activity of neuroserpin against NMDA receptor-mediated excitotoxicity." Journal of Cerebral Blood Flow & Metabolism 25, no. 1_suppl (August 2005): S455. http://dx.doi.org/10.1038/sj.jcbfm.9591524.0455.

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40

Perucci, Luiza Oliveira, Sirlaine Pio Gomes da Silva, Eduardo Bearzoti, Kelerson Mauro de Castro Pinto, Patrícia Nessralla Alpoim, Melina de Barros Pinheiro, Lara Carvalho Godoi, et al. "Neuroserpin: A potential biomarker for early-onset severe preeclampsia." Immunobiology 228, no. 2 (March 2023): 152339. http://dx.doi.org/10.1016/j.imbio.2023.152339.

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41

Belorgey, Didier, Damian C. Crowther, Ravi Mahadeva, and David A. Lomas. "Mutant Neuroserpin (S49P) That Causes Familial Encephalopathy with Neuroserpin Inclusion Bodies Is a Poor Proteinase Inhibitor and Readily Forms Polymers in Vitro." Journal of Biological Chemistry 277, no. 19 (May 2002): 17367–73. http://dx.doi.org/10.1074/jbc.m200680200.

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42

Cuadrado, A. "HuD binds to three AU-rich sequences in the 3'-UTR of neuroserpin mRNA and promotes the accumulation of neuroserpin mRNA and protein." Nucleic Acids Research 30, no. 10 (May 15, 2002): 2202–11. http://dx.doi.org/10.1093/nar/30.10.2202.

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43

Kaiserman, Dion, James C. Whisstock, and Phillip I. Bird. "Mechanisms of serpin dysfunction in disease." Expert Reviews in Molecular Medicine 8, no. 31 (December 2006): 1–19. http://dx.doi.org/10.1017/s1462399406000184.

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The serpin superfamily encompasses hundreds of proteins, spread across all kingdoms of life, linked by a common tertiary fold. This review focuses on five diseases caused by serpin dysfunction: variants of antithrombin III lose their ability to interact with heparin; the α1-antitrypsin Pittsburgh mutation causes a change in target proteinase; the α1-antitrypsin Z mutation and neuroserpin, polymerisation of which lead to cellular cytotoxicity; and a loss of maspin expression resulting in cancer.

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44

Coutelier, M., S. Andries, S. Ghariani, B. Dan, C. Duyckaerts, K. van Rijckevorsel, C. Raftopoulos, et al. "NEUROSERPIN MUTATION CAUSES ELECTRICAL STATUS EPILEPTICUS OF SLOW-WAVE SLEEP." Neurology 71, no. 1 (June 30, 2008): 64–66. http://dx.doi.org/10.1212/01.wnl.0000316306.08751.28.

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45

Yazaki, Masahide, Juris J. Liepnieks, Jill R. Murrell, Masaki Takao, Brian Guenther, Pedro Piccardo, Martin R. Farlow, Bernardino Ghetti, and Merrill D. Benson. "Biochemical Characterization of a Neuroserpin Variant Associated with Hereditary Dementia." American Journal of Pathology 158, no. 1 (January 2001): 227–33. http://dx.doi.org/10.1016/s0002-9440(10)63961-2.

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46

Ricagno, Stefano, Margherita Pezzullo, Alberto Barbiroli, Mauro Manno, Matteo Levantino, Maria Grazia Santangelo, Francesco Bonomi, and Martino Bolognesi. "Two Latent and Two Hyperstable Polymeric Forms of Human Neuroserpin." Biophysical Journal 99, no. 10 (November 2010): 3402–11. http://dx.doi.org/10.1016/j.bpj.2010.09.021.

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Schrimpf, Sabine P., Andreas J. Bleiker, Lukrecija Brecevic, Serguei V. Kozlov, Philipp Berger, Thomas Osterwalder, Stefan R. Krueger, Albert Schinzel, and Peter Sonderegger. "Human Neuroserpin (PI12): cDNA Cloning and Chromosomal Localization to 3q26." Genomics 40, no. 1 (February 1997): 55–62. http://dx.doi.org/10.1006/geno.1996.4514.

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Parmar, Parmjeet K., Leigh C. Coates, John F. Pearson, Rena M. Hill, and Nigel P. Birch. "Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells." Journal of Neurochemistry 82, no. 6 (September 19, 2002): 1406–15. http://dx.doi.org/10.1046/j.1471-4159.2002.01100.x.

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Mohsenifar, Afshin, Habib Nazem, and Sahar Majdi. "Chitosan-myristate nanogel as an artificial chaperone protects neuroserpin from misfolding." Advanced Biomedical Research 5, no. 1 (2016): 170. http://dx.doi.org/10.4103/2277-9175.190942.

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de Groot, Dorien M., Christine Pol, and Gerard J. M. Martens. "Comparative Analysis and Expression of Neuroserpin in Xenopus laevis." Neuroendocrinology 82, no. 1 (2005): 11–20. http://dx.doi.org/10.1159/000090011.

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Journal articles on the topic 'Neuroserpin'

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