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Cited by 30Alzheimer's disease research and treatmentsEndoplasmic Reticulum Stress and DiseaseGenetic Neurodegenerative Diseases

Neuroserpin polymers cause oxidative stress in a neuronal model of the dementia FENIB

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Guadagno, Noemi A., Moriconi, Claudia, Licursi, Valerio, D'Acunto, Emanuela, Nisi, Paola S., Carucci, Nicoletta, De Jaco, Antonella, Cacci, Emanuele +3 more·2017·Neurobiology of Disease
DOI 10.1016/j.nbd.2017.03.010PMC PMC5439028
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Abstract

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. We have characterised these cell lines in the proliferative state and after differentiation to neurons. Our results show that G392E NS formed polymers that were mostly retained within the ER, while wild type NS was correctly secreted as a monomeric protein into the culture medium. Delta NS was absent at steady state due to its rapid degradation, but it was easily detected upon proteasomal block. Looking at their intracellular distribution, wild type NS was found in partial co-localisation with ER and Golgi markers, while G392E NS was localised within the ER only. Furthermore, polymers of NS were detected by ELISA and immunofluorescence in neurons expressing the mutant but not the wild type protein. We used control GFP and G392E NPCs differentiated to neurons to investigate which cellular pathways were modulated by intracellular polymers by performing RNA sequencing. We identified 747 genes with a significant upregulation (623) or downregulation (124) in G392E NS-expressing cells, and we focused our attention on several genes involved in the defence against oxidative stress that were up-regulated in cells expressing G392E NS (Aldh1b1, Apoe, Gpx1, Gstm1, Prdx6, Scara3, Sod2). Inhibition of intracellular anti-oxidants by specific pharmacological reagents uncovered the damaging effects of NS polymers. Our results support a role for oxidative stress in the cellular toxicity underlying the neurodegenerative dementia FENIB.

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  • Expression of a mutant form of neuroserpin in mouse neural progenitor cells activates a transcriptional signature (M205) that significantly overlapped with cluster A module IF-Gyellow (padj = 8.1 × 10−17) as well as FPblue (padj = 4.7 × 10−6).

    “In another example, expression of a mutant form of neuroserpin in mouse neural progenitor cells (Guadagno et al., 2017) activates a transcriptional signature (M205) that significantly overlapped with cluster A module IF-Gyellow (padj = 8.1 × 10−17) as well as FPblue (Figure 5B; padj = 4.7 × 10−6), a cluster D module showing some selectivity for AD transgenic models (above).”

    From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Guadagno et al., 2017

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Research works printed but not linked: 43

  1. Ashburner M. Ball C.A. Blake J.A. Botstein D. Butler H. Cherry J.M. Davis A.P. Dolinski K. Dwight S.S. Eppig J.T. Harris M.A. Hill D.P. Issel-Tarver L. Kasarskis A. Lewis S. Matese J.C. Richardson J.E. Ringwald M. Rubin G.M. Sherlock G. Gene ontology: tool for the unification of biology. The gene ontology consortium Nat. Genet. 25 2000 25 29 10802651 PMC3037419
  2. Brown C.O. Schibler J. Fitzgerald M.P. Singh N. Salem K. Zhan F. Goel A. Scavenger receptor class A member 3 (SCARA3) in disease progression and therapy resistance in multiple myeloma Leuk. Res. 37 2013 963 969 23537707 PMC3700682
  3. Cheng Y. Loh Y.P. Birch N.P. Neuroserpin attenuates H2O2-induced oxidative stress in hippocampal neurons via AKT and BCL-2 signaling pathways J. Mol. Neurosci. MN. 2016 27510267
  4. Cobb C.A. Cole M.P. Oxidative and nitrative stress in neurodegeneration Neurobiol. Dis. 84 2015 4 21 26024962 PMC4662638
  5. Conti L. Pollard S.M. Gorba T. Reitano E. Toselli M. Biella G. Sun Y. Sanzone S. Ying Q.-L. Cattaneo E. Smith A. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell PLoS Biol. 3 2005 e283 PMC1184591 16086633
  6. Coutelier M. Andries S. Ghariani S. Dan B. Duyckaerts C. van Rijckevorsel K. Raftopoulos C. Deconinck N. Sonderegger P. Scaravilli F. Vikkula M. Godfraind C. Neuroserpin mutation causes electrical status epilepticus of slow-wave sleep Neurology 71 2008 64 66 18591508
  7. Croft D. Mundo A.F. Haw R. Milacic M. Weiser J. Wu G. Caudy M. Garapati P. Gillespie M. Kamdar M.R. Jassal B. Jupe S. Matthews L. May B. Palatnik S. Rothfels K. Shamovsky V. Song H. Williams M. Birney E. Hermjakob H. Stein L. D'Eustachio P. The reactome pathway knowledgebase Nucleic Acids Res. 42 2014 D472 D477 24243840 PMC3965010
  8. Davies M.J. Miranda E. Roussel B.D. Kaufman R.J. Marciniak S.J. Lomas D.A. Neuroserpin polymers activate NF-kappaB by a calcium signaling pathway that is independent of the unfolded protein response J. Biol. Chem. 284 2009 18202 18209 19423713 PMC2709363
  9. Davis R.L. Shrimpton A.E. Holohan P.D. Bradshaw C. Feiglin D. Collins G.H. Sonderegger P. Kinter J. Becker L.M. Lacbawan F. Krasnewich D. Muenke M. Lawrence D.A. Yerby M.S. Shaw C.M. Gooptu B. Elliott P.R. Finch J.T. Carrell R.W. Lomas D.A. Familial dementia caused by polymerization of mutant neuroserpin Nature 401 1999 376 379 10517635
  10. Davis R.L. Shrimpton A.E. Carrell R.W. Lomas D.A. Gerhard L. Baumann B. Lawrence D.A. Yepes M. Kim T.S. Ghetti B. Piccardo P. Takao M. Lacbawan F. Muenke M. Sifers R.N. Bradshaw C.B. Kent P.F. Collins G.H. Larocca D. Holohan P.D. Association between conformational mutations in neuroserpin and onset and severity of dementia Lancet Lond. Engl. 359 2002 2242 2247 12103288
  11. Dringen R. Pawlowski P.G. Hirrlinger J. Peroxide detoxification by brain cells J. Neurosci. Res. 79 2005 157 165 15573410
  12. Galliciotti G. Glatzel M. Kinter J. Kozlov S.V. Cinelli P. Rülicke T. Sonderegger P. Accumulation of mutant neuroserpin precedes development of clinical symptoms in familial encephalopathy with neuroserpin inclusion bodies Am. J. Pathol. 170 2007 1305 1313 17392169 PMC1829463
  13. Gandhi S. Abramov A.Y. Mechanism of oxidative stress in neurodegeneration Oxidative Med. Cell. Longev. 2012 2012 428010 PMC3362933 22685618
  14. Gentleman R.C. Carey V.J. Bates D.M. Bolstad B. Dettling M. Dudoit S. Ellis B. Gautier L. Ge Y. Gentry J. Hornik K. Hothorn T. Huber W. Iacus S. Irizarry R. Leisch F. Li C. Maechler M. Rossini A.J. Sawitzki G. Smith C. Smyth G. Tierney L. Yang J.Y.H. Zhang J. Bioconductor: open software development for computational biology and bioinformatics Genome Biol. 5 2004 R80 15461798 PMC545600
  15. Hagen M.C. Murrell J.R. Delisle M.-B. Andermann E. Andermann F. Guiot M.C. Ghetti B. Encephalopathy with neuroserpin inclusion bodies presenting as progressive myoclonus epilepsy and associated with a novel mutation in the proteinase inhibitor 12 gene Brain Pathol. 21 2011 575 582 21435071 PMC3709456
  16. Han H.J. Tokino T. Nakamura Y. CSR, a scavenger receptor-like protein with a protective role against cellular damage causedby UV irradiation and oxidative stress Hum. Mol. Genet. 7 1998 1039 1046 9580669
  17. Kroeger H. Miranda E. MacLeod I. Pérez J. Crowther D.C. Marciniak S.J. Lomas D.A. Endoplasmic reticulum-associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins J. Biol. Chem. 284 2009 22793 22802 19549782 PMC2755687
  18. Lawless M.W. Greene C.M. Mulgrew A. Taggart C.C. O'Neill S.J. McElvaney N.G. Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency J. Immunol. 1950 172 2004 5722 5726 15100318
  19. Li J.O.W. Li W. Jiang Z.-G. Ghanbari H.A. Oxidative stress and neurodegenerative disorders Int. J. Mol. Sci. 14 2013 24438 24475 24351827 PMC3876121
  20. Love M.I. Huber W. Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 15 2014 550 25516281 PMC4302049
  21. Luo W. Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization Bioinforma 29 2013 1830 1831 PMC3702256 23740750
  22. Makia N.L. Bojang P. Falkner K.C. Conklin D.J. Prough R.A. Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation Chem. Biol. Interact. 191 2011 278 287 21256123 PMC4409133
  23. Malhotra J.D. Kaufman R.J. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid. Redox Signal. 9 2007 2277 2293 17979528
  24. Marcus N.Y. Blomenkamp K. Ahmad M. Teckman J.H. Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency Exp. Biol. Med. 237 2012 1163 1172 (Maywood NJ) PMC3510980 23104507
  25. Margoliash E. Novogrodsky A. Schejter A. Irreversible reaction of 3-amino-1:2:4-triazole and related inhibitors with the protein of catalase Biochem. J. 74 1960 339 348 13848609 PMC1204166
  26. Miranda E. Römisch K. Lomas D.A. Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum J. Biol. Chem. 279 2004 28283 28291 15090543
  27. Miranda E. MacLeod I. Davies M.J. Pérez J. Römisch K. Crowther D.C. Lomas D.A. The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB Hum. Mol. Genet. 17 2008 1527 1539 18267959 PMC2387220
  28. Mitchell J.B. Russo A. Biaglow J.E. McPherson S. Cellular glutathione depletion by diethyl maleate or buthionine sulfoximine: no effect of glutathione depletion on the oxygen enhancement ratio Radiat. Res. 96 1983 422 428 6647769
  29. Montine T.J. Montine K.S. Olson S.J. Graham D.G. Roberts L.J. Morrow J.D. Linton M.F. Fazio S. Swift L.L. Increased cerebral cortical lipid peroxidation and abnormal phospholipids in aged homozygous apoE-deficient C57BL/6J mice Exp. Neurol. 158 1999 234 241 10448437
  30. Moriconi C. Ordoñez A. Lupo G. Gooptu B. Irving J.A. Noto R. Martorana V. Manno M. Timpano V. Guadagno N.A. Dalton L. Marciniak S.J. Lomas D.A. Miranda E. Interactions between N-linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum FEBS J. 282 2015 4565 4579 26367528 PMC4949553
  31. Ordóñez A. Snapp E.L. Tan L. Miranda E. Marciniak S.J. Lomas D.A. Endoplasmic reticulum polymers impair luminal protein mobility and sensitize to cellular stress in alpha1-antitrypsin deficiency Hepatol. Baltim. Md 57 2013 2049 2060 PMC3871212 23197448
  32. Power J.H.T. Shannon J.M. Blumbergs P.C. Gai W.-P. Nonselenium glutathione peroxidase in human brain: elevated levels in Parkinson's disease and dementia with lewy bodies Am. J. Pathol. 161 2002 885 894 12213717 PMC1867235
  33. Power J.H.T. Asad S. Chataway T.K. Chegini F. Manavis J. Temlett J.A. Jensen P.H. Blumbergs P.C. Gai W.-P. Peroxiredoxin 6 in human brain: molecular forms, cellular distribution and association with Alzheimer's disease pathology Acta Neuropathol. 115 2008 611 622 (Berl.) 18386021 PMC2386158
  34. Pratt T. Sharp L. Nichols J. Price D.J. Mason J.O. Embryonic stem cells and transgenic mice ubiquitously expressing a tau-tagged green fluorescent protein Dev. Biol. 228 2000 19 28 11087623
  35. Roussel B.D. Irving J.A. Ekeowa U.I. Belorgey D. Haq I. Ordóñez A. Kruppa A.J. Duvoix A. Rashid S.T. Crowther D.C. Marciniak S.J. Lomas D.A. Unravelling the twists and turns of the serpinopathies FEBS J. 278 2011 3859 3867 21624056
  36. Roussel B.D. Newton T.M. Malzer E. Simecek N. Haq I. Thomas S.E. Burr M.L. Lehner P.J. Crowther D.C. Marciniak S.J. Lomas D.A. Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB Hum. Mol. Genet. 22 2013 4616 4626 23814041 PMC3889810
  37. Schulz J.B. Lindenau J. Seyfried J. Dichgans J. Glutathione, oxidative stress and neurodegeneration Eur. J. Biochem. 267 2000 4904 4911 (FEBS) 10931172
  38. Sharma R. Yang Y. Sharma A. Awasthi S. Awasthi Y.C. Antioxidant role of glutathione S-transferases: protection against oxidant toxicity and regulation of stress-mediated apoptosis Antioxid. Redox Signal. 6 2004 289 300 15025930
  39. Sinno M. Biagioni S. Ajmone-Cat M.A. Pafumi I. Caramanica P. Medda V. Tonti G. Minghetti L. Mannello F. Cacci E. The matrix metalloproteinase inhibitor marimastat promotes neural progenitor cell differentiation into neurons by gelatinase-independent TIMP-2-dependent mechanisms Stem Cells Dev. 22 2013 345 358 23098139
  40. Soldati C. Cacci E. Biagioni S. Carucci N. Lupo G. Perrone-Capano C. Saggio I. Augusti-Tocco G. Restriction of neural precursor ability to respond to Nurr1 by early regional specification PLoS One 7 2012 e51798 PMC3519900 23240065
  41. Trapnell C. Roberts A. Goff L. Pertea G. Kim D. Kelley D.R. Pimentel H. Salzberg S.L. Rinn J.L. Pachter L. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and cufflinks Nat. Protoc. 7 2012 562 578 22383036 PMC3334321
  42. Vallier L. Rugg-Gunn P.J. Bouhon I.A. Andersson F.K. Sadler A.J. Pedersen R.A. Enhancing and diminishing gene function in human embryonic stem cells Stem Cells 22 2004 2 11 (Dayt. Ohio) 14688386
  43. Yu G. Wang L.-G. Han Y. He Q.-Y. clusterProfiler: an R package for comparing biological themes among gene clusters Omics J. Integr. Biol. 16 2012 284 287 PMC3339379 22455463

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Authors
Guadagno, N. A., Moriconi, C., Licursi, V., D'Acunto, E., Nisi, P. S., Carucci, N., De Jaco, A., Cacci, E., Negri, R., Lupo, G., & Miranda, E.
Affiliations
  • Sapienza University of Rome (IT)
  • National Research Council (IT)
  • Institute of Molecular Biology and Pathology (IT)
  • Istituto Pasteur (IT)
Corresponding author
  • Lupo, Giuseppe
  • Miranda, Elena
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2017-07
Volume
103
Pages
32-44
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2017.03.010
PMC
PMC5439028
OpenAlex
W2598241518
Cited by
30
References
0
Citations by year
2025: 2 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 2 · 2018: 2 · 2017: 2
FWCI
2.33
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fondazione Telethon (GGP11057)
  • Sapienza Università di Roma
  • Istituto Pasteur-Fondazione Cenci Bolognetti (under 40)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
neuroserpin, serpinopathies, oxidative stress, neurodegeneration, endoplasmic reticulum, neuronal differentiation, proteasomal degradation, antioxidant gene expression, Alzheimer's disease
MeSH terms
Neuroserpin, Animals, Cell Survival, Cells, Cultured, Cerebral Cortex, Dementia, Epilepsies, Myoclonic, Humans, Mice, Transgenic, Neurons, Neuropeptides, Polymers, Serpins, Oxidative Stress, Heredodegenerative Disorders, Nervous System, Mice

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