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Noemi A Guadagno, Claudia Moriconi, Valerio Licursi, Emanuela D'Acunto, Paola S Nisi, Nicoletta Carucci, Antonella De Jaco, Emanuele Cacci, Rodolfo Negri, Giuseppe Lupo, Elena Miranda
The serpinopathies are human pathologies caused by mutations that promote polymerisation and intracellular deposition of proteins of the serpin superfamily, leading to a poorly understood cell toxicity. The dementia FENIB is caused by polymerisation of the neuronal serpin neuroserpin (NS) within the endoplasmic reticulum (ER) of neurons. With the aim of understanding the toxicity due to intracellular accumulation of neuroserpin polymers, we have generated transgenic neural progenitor cell (NPC) cultures from mouse foetal cerebral cortex, stably expressing the control protein GFP (green fluorescent protein), or human wild type, G392E or delta NS...
March 28, 2017: Neurobiology of Disease
Costanza Giampietro, Maria Chiara Lionetti, Giulio Costantini, Federico Mutti, Stefano Zapperi, Caterina A M La Porta
Intraneural accumulation of misfolded proteins is a common feature of several neurodegenerative pathologies including Alzheimer's and Parkinson's diseases, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is a rare disease due to a point mutation in neuroserpin which accelerates protein aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol depletion induced either by prolonged exposure to statins or by inhibiting the sterol reg-ulatory binding-element protein (SREBP) pathway also enhances aggregation of neuroserpin proteins...
March 3, 2017: Scientific Reports
Minna Saaristo, Bob B M Wong, Laura Mincarelli, Allison Craig, Christopher P Johnstone, Mayumi Allinson, Kai Lindström, John A Craft
Waterways are increasingly being contaminated by chemical compounds that can disrupt the endocrinology of organisms. One such compound is 17α-ethinyl estradiol (EE2), a synthetic estrogen used in the contraceptive pill. Despite considerable research interest in the effects of EE2 on reproduction and gene expression, surprisingly, only a few studies have capitalised on technologies, such as next-generation sequencing (NGS), to uncover the molecular pathways related to EE2 exposure. Accordingly, using high-throughput sequencing technologies, the aim of our study was to explore the effects of EE2 on brain transcriptome in wild-type male and female guppy (Poecilia reticulata)...
February 16, 2017: Aquatic Toxicology
R D Idell, G Florova, A A Komissarov, S Shetty, R B S Girard, S Idell
Current understanding of the neurobiology of depression has grown over the past few years beyond the traditional monoamine theory of depression to include chronic stress, inflammation and disrupted synaptic plasticity. Tissue plasminogen activator (tPA) is a key factor that not only promotes fibrinolysis via the activation of plasminogen, but also contributes to regulation of synaptic plasticity and neurogenesis through plasmin-mediated activation of a probrain derived neurotrophic factor (BDNF) to mature BDNF...
March 2017: Medical Hypotheses
Mohammad Farhan Ali, Abhinav Kaushik, Charu Kapil, Dinesh Gupta, Mohamad Aman Jairajpuri
Neuroserpin (NS) mediated inhibition of tissue-type plasminogen activator (tPA) is important for brain development, synapse formation and memory. Aberrations in helix F and β-sheet A movement during inhibition can directly lead to epilepsy or dementia. Conserved W154 residue in a hydrophobic patch between helix F and β-sheet A is ideally placed to control their movement during inhibition. Molecular Dynamics (MD) simulation on wild type (WT) NS and its two variants (W154A and W154P) demonstrated partial deformation in helix F and conformational differences in strands 1A and 2A only in W154P...
February 23, 2017: Scientific Reports
Takayuki Iwaki, Kotomi Nagahashi, Katsuhiro Takano, Katsue Suzuki-Inoue, Naohiro Kanayama, Kazuo Umemura, Tetsumei Urano
Serpinopathy is characterised as abnormal accumulation of serine protease inhibitors (SERPINs) in cells and results in clinical symptoms owing to lack of SERPIN function or excessive accumulation of abnormal SERPIN. We recently identified a patient with functional deficiency of plasminogen activator inhibitor-1 (PAI-1), a member of the SERPIN superfamily. The patient exhibited life-threatening bleeding tendencies, which have also been observed in patients with a complete deficiency in PAI-1. Sequence analysis revealed a homozygous single-nucleotide substitution from guanine to cytosine at exon 9, which changed amino acid residue 397 from glycine to arginine (c...
February 23, 2017: Thrombosis and Haemostasis
Habib Nazem, Afshin Mohsenifar, Sahar Majdi
BACKGROUND: Molecular chaperon-like activity for protein refolding was studied using nanogel chitosan-myristic acid (CMA) and the protein neuroserpin (NS), a member of the serine proteinase inhibitor superfamily (serpin). MATERIALS AND METHODS: Recombinant his-tag fusion NS was expressed in Escherichia coli. For confirmation of refolding of the purified NS, structural analysis was performed by circular dichroism and spectrofluorometric along with its inhibitory activity, which was assayed by single-chain tissue plasminogen activator...
2016: Advanced Biomedical Research
Tet Woo Lee, Vicky W K Tsang, Evert Jan Loef, Nigel P Birch
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...
February 2017: Seminars in Cell & Developmental Biology
Benoit D Roussel, David A Lomas, Damian C Crowther
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...
September 1, 2016: Epileptic Disorders: International Epilepsy Journal with Videotape
Yong Cheng, Y Peng Loh, Nigel P Birch
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...
January 2017: Journal of Molecular Neuroscience: MN
M Florencia Iulita, Alison Ower, Concetta Barone, Rowan Pentz, Palma Gubert, Corrado Romano, Rita Anna Cantarella, Flaviana Elia, Serafino Buono, Marilena Recupero, Carmelo Romano, Sabrina Castellano, Paolo Bosco, Santo Di Nuovo, Filippo Drago, Filippo Caraci, A Claudio Cuello
INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Aβ, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Aβ40 and Aβ42 were elevated in DS plasma compared to controls, even in DS individuals without dementia...
July 21, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Karen-Sue B Carlson, Lan Nguyen, Kat Schwartz, Daniel A Lawrence, Bradford S Schwartz
Tissue-type plasminogen activator (t-PA), initially characterized for its critical role in fibrinolysis, also has key functions in both physiologic and pathologic processes in the CNS. Neuroserpin (NSP) is a t-PA specific serine protease inhibitor (serpin) found almost exclusively in the CNS that regulates t-PA's proteolytic activity and protects against t-PA mediated seizure propagation and blood-brain barrier disruption. This report demonstrates that NSP inhibition of t-PA varies profoundly as a function of pH within the biologically relevant pH range for the CNS, and reflects the stability, rather than the formation of NSP: t-PA acyl-enzyme complexes...
2016: Frontiers in Cellular Neuroscience
Natalie Lorenz, Evert Jan Loef, Inken D Kelch, Daniel J Verdon, Moyra M Black, Martin J Middleditch, David R Greenwood, E Scott Graham, Anna Es Brooks, P Rod Dunbar, Nigel P Birch
The homeostatic chemokine CCL21 has a pivotal role in lymphocyte homing and compartment localisation within the lymph node, and also affects adhesion between immune cells. The effects of CCL21 are modulated by its mode of presentation, with different cellular responses seen for surface-bound and soluble forms. Here we show that plasmin cleaves surface-bound CCL21 to release the C-terminal peptide responsible for CCL21 binding to glycosaminoglycans on the extracellular matrix and cell surfaces, thereby generating the soluble form...
November 2016: Immunology and Cell Biology
Xuelian Yang, Tetsuya Asakawa, Sha Han, Ling Liu, Wei Li, Weiwen Wu, Yunhe Luo, Wenjie Cao, Xin Cheng, Baoguo Xiao, Hiroki Namba, Chuanzhen Lu, Qiang Dong, Liang Wang
BACKGROUND/AIMS: Neuroserpin (NSP) is known for its neuroprotective role in cerebral ischemic animal models and patients. Our laboratory conducted a series of investigations on the neuroprotection of NSP in different cells in the brain. In the present study, we further observe the effects of NSP on neurons and microglia-mediated inflammatory response following oxygen-glucose deprivation (OGD), and explore possible mechanisms related to neuroprotection of OGD in the central nervous system (CNS)...
2016: Cellular Physiology and Biochemistry
Irene López-González, Alberto Pérez-Mediavilla, Marta Zamarbide, Margarita Carmona, Benjamin Torrejón Escribano, Markus Glatzel, Giovanna Galliciotti, Isidre Ferrer
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare disease characterized by the deposition of multiple intracytoplasmic neuronal inclusions that contain mutated neuroserpin. Tg-Syracuse (Tg-Syr) mice express Ser49Pro mutated neuroserpin and develop clinical and neuropathological features of human FENIB. We used 8-, 34-, 45- and 80-week-old Tg-Syr mice to characterize neuroinflammation and the unfolded protein response (UPR) in a neurodegenerative disease in which abnormal protein aggregates accumulate within the endoplasmic reticulum (ER)...
February 2016: Journal of Neuropathology and Experimental Neurology
Giorgia Saga, Fabio Sessa, Alberto Barbiroli, Carlo Santambrogio, Rosaria Russo, Michela Sala, Samuele Raccosta, Vincenzo Martorana, Sonia Caccia, Rosina Noto, Claudia Moriconi, Elena Miranda, Rita Grandori, Mauro Manno, Martino Bolognesi, Stefano Ricagno
Neuroserpin (NS) is a serpin inhibitor of tissue plasminogen activator (tPA) in the brain. The polymerisation of NS pathologic mutants is responsible for a genetic dementia known as familial encephalopathy with neuroserpin inclusion bodies (FENIB). So far, a pharmacological treatment of FENIB, i.e. an inhibitor of NS polymerisation, remains an unmet challenge. Here, we present a biophysical characterisation of the effects caused by embelin (EMB a small natural compound) on NS conformers and NS polymerisation...
January 6, 2016: Scientific Reports
Sriram Ambadapadi, Ganesh Munuswamy-Ramanujam, Donghang Zheng, Colin Sullivan, Erbin Dai, Sufi Morshed, Baron McFadden, Emily Feldman, Melissa Pinard, Robert McKenna, Scott Tibbetts, Alexandra Lucas
Serpins regulate coagulation and inflammation, binding serine proteases in suicide-inhibitory complexes. Target proteases cleave the serpin reactive center loop scissile P1-P1' bond, resulting in serpin-protease suicide-inhibitory complexes. This inhibition requires a near full-length serpin sequence. Myxomavirus Serp-1 inhibits thrombolytic and thrombotic proteases, whereas mammalian neuroserpin (NSP) inhibits only thrombolytic proteases. Both serpins markedly reduce arterial inflammation and plaque in rodent models after single dose infusion...
February 5, 2016: Journal of Biological Chemistry
Jochen Weigele, Tamara A Franz-Odendaal, Reinhard Hilbig
The fish ear stones (otoliths) consist mainly of calcium carbonate and have lower amounts of a proteinous matrix. This matrix consists of macromolecules, which directly control the biomineralization process. We analyzed the composition of this proteinous matrix by mass spectrometry in a shotgun approach. For this purpose, an enhanced protein purification technique was developed that excludes any potential contamination of proteins from body fluids. Using this method we identified eight proteins in the inner ear of Oreochromis mossambicus...
February 2016: Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology
Tet Woo Lee, Vicky W K Tsang, Nigel P Birch
Although its roles in the vascular space are most well-known, tissue plasminogen activator (tPA) is widely expressed in the developing and adult nervous system, where its activity is believed to be regulated by neuroserpin, a predominantly brain-specific member of the serpin family of protease inhibitors. In the normal physiological state, tPA has been shown to play roles in the development and plasticity of the nervous system. Ischemic damage, however, may lead to excess tPA activity in the brain and this is believed to contribute to neurodegeneration...
2015: Frontiers in Cellular Neuroscience
Claudia Moriconi, Adriana Ordoñez, Giuseppe Lupo, Bibek Gooptu, James A Irving, Rosina Noto, Vincenzo Martorana, Mauro Manno, Valentina Timpano, Noemi A Guadagno, Lucy Dalton, Stefan J Marciniak, David A Lomas, Elena Miranda
The neuronal serpin neuroserpin undergoes polymerisation as a consequence of point mutations that alter its conformational stability, leading to a neurodegenerative dementia called familial encephalopathy with neuroserpin inclusion bodies (FENIB). Neuroserpin is a glycoprotein with predicted glycosylation sites at asparagines 157, 321 and 401. We used site-directed mutagenesis, transient transfection, western blot, metabolic labelling and ELISA to probe the relationship between glycosylation, folding, polymerisation and degradation of neuroserpin in validated cell models of health and disease...
December 2015: FEBS Journal
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