Login Register Cart 0
Generic placeholder image

Current Neuropharmacology

Editor-in-Chief

ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Research Article

Molecular Connections between DNA Replication and Cell Death in β-Amyloid-Treated Neurons

Author(s): Filippo Caraci, Annamaria Fidilio, Rosa Santangelo, Giuseppe Caruso, Maria Laura Giuffrida, Marianna Flora Tomasello, Ferdinando Nicoletti and Agata Copani*

Volume 21, Issue 9, 2023

Published on: 05 April, 2023

Page: [2006 - 2018] Pages: 13

DOI: 10.2174/1570159X21666230404121903

Price: $65

Abstract

Background: Ectopic cell cycle reactivation in neurons is associated with neuronal death in Alzheimer’s disease. In cultured rodent neurons, synthetic β-amyloid (Aβ) reproduces the neuronal cell cycle re-entry observed in the Alzheimer’s brain, and blockade of the cycle prevents Aβ-induced neurodegeneration. DNA polymerase-β, whose expression is induced by Aβ, is responsible for the DNA replication process that ultimately leads to neuronal death, but the molecular mechanism(s) linking DNA replication to neuronal apoptosis are presently unknown.

Aim: To explore the role of a conserved checkpoint pathway started by DNA replication stress, namely the ATM-ATR/Claspin/Chk-1 pathway, in switching the neuronal response from DNA replication to apoptosis.

Methods: Experiments were carried out in cultured rat cortical neurons challenged with toxic oligomers of Aβ protein.

Results: Small inhibitory molecules of ATM/ATR kinase or Chk-1 amplified Aβ-induced neuronal DNA replication and apoptosis, as they were permissive to the DNA polymerase-β activity triggered by Aβ oligomers. Claspin, i.e., the adaptor protein between ATM/ATR kinase and the downstream Chk-1, was present on DNA replication forks of neurons early after Aβ challenge, and decreased at times coinciding with neuronal apoptosis. The caspase-3/7 inhibitor I maintained overtime the amount of Claspin loaded on DNA replication forks and, concomitantly, reduced neuronal apoptosis by holding neurons in the S phase. Moreover, a short phosphopeptide mimicking the Chk-1-binding motif of Claspin was able to prevent Aβ-challenged neurons from entering apoptosis.

Conclusion: We speculate that, in the Alzheimer’s brain, Claspin degradation by intervening factors may precipitate the death of neurons engaged into DNA replication.

« Previous
Graphical Abstract

[1]
Herrup, K.; Neve, R.; Ackerman, S.L.; Copani, A. Divide and die: Cell cycle events as triggers of nerve cell death. J. Neurosci., 2004, 24(42), 9232-9239.
[http://dx.doi.org/10.1523/JNEUROSCI.3347-04.2004] [PMID: 15496657]
[2]
Höglinger, G.U.; Breunig, J.J.; Depboylu, C.; Rouaux, C.; Michel, P.P.; Alvarez-Fischer, D.; Boutillier, A.L.; DeGregori, J.; Oertel, W.H.; Rakic, P.; Hirsch, E.C.; Hunot, S. The pRb/E2F cell-cycle pathway mediates cell death in Parkinson’s disease. Proc. Natl. Acad. Sci. USA, 2007, 104(9), 3585-3590.
[http://dx.doi.org/10.1073/pnas.0611671104] [PMID: 17360686]
[3]
Pelegrí, C.; Duran-Vilaregut, J.; Valle, J.; Crespo-Biel, N.; Ferrer, I.; Pallàs, M.; Camins, A.; Vilaplana, J. Cell cycle activation in striatal neurons from Huntington’s disease patients and rats treated with 3-nitropropionic acid. Int. J. Dev. Neurosci., 2008, 26(7), 665-671.
[http://dx.doi.org/10.1016/j.ijdevneu.2008.07.016] [PMID: 18768156]
[4]
Ranganathan, S.; Bowser, R. Alterations in G(1) to S phase cell-cycle regulators during amyotrophic lateral sclerosis. Am. J. Pathol., 2003, 162(3), 823-835.
[http://dx.doi.org/10.1016/S0002-9440(10)63879-5] [PMID: 12598317]
[5]
Yang, Y.; Geldmacher, D.S.; Herrup, K. DNA replication precedes neuronal cell death in Alzheimer’s disease. J. Neurosci., 2001, 21(8), 2661-2668.
[http://dx.doi.org/10.1523/JNEUROSCI.21-08-02661.2001] [PMID: 11306619]
[6]
Copani, A.; Condorelli, F.; Caruso, A.; Vancheri, C.; Sala, A.; Stella, A.M.G.; Canonico, P.L.; Nicoletti, F.; Sortino, M.A. Mitotic signaling by β-amyloid causes neuronal death. FASEB J., 1999, 13(15), 2225-2234.
[http://dx.doi.org/10.1096/fasebj.13.15.2225] [PMID: 10593870]
[7]
Copani, A.; Sortino, M.A.; Caricasole, A.; Chiechio, S.; Chisari, M.; Battaglia, G.; Giuffrida-Stella, A.M.; Vancheri, C.; Nicoletti, F. Erratic expression of DNA polymerases by β-amyloid causes neuronal death. FASEB J., 2002, 16(14), 2006-2008.
[http://dx.doi.org/10.1096/fj.02-0422fje] [PMID: 12397084]
[8]
Copani, A.; Hoozemans, J.J.M.; Caraci, F.; Calafiore, M.; Van Haastert, E.S.; Veerhuis, R.; Rozemuller, A.J.M.; Aronica, E.; Sortino, M.A.; Nicoletti, F. DNA polymerase-beta is expressed early in neurons of Alzheimer’s disease brain and is loaded into DNA replication forks in neurons challenged with beta-amyloid. J. Neurosci., 2006, 26(43), 10949-10957.
[http://dx.doi.org/10.1523/JNEUROSCI.2793-06.2006] [PMID: 17065437]
[9]
Copani, A.; Caraci, F.; Hoozemans, J.J.M.; Calafiore, M.; Angela Sortino, M.; Nicoletti, F. The nature of the cell cycle in neurons: Focus on a “non-canonical” pathway of DNA replication causally related to death. Biochim. Biophys. Acta Mol. Basis Dis., 2007, 1772(4), 409-412.
[http://dx.doi.org/10.1016/j.bbadis.2006.10.016] [PMID: 17196375]
[10]
Merlo, S.; Basile, L.; Giuffrida, M.L.; Sortino, M.A.; Guccione, S.; Copani, A. Identification of 5-methoxyflavone as a novel DNA polymerase-beta inhibitor and neuroprotective agent against beta-amyloid toxicity. J. Nat. Prod., 2015, 78(11), 2704-2711.
[http://dx.doi.org/10.1021/acs.jnatprod.5b00621] [PMID: 26517378]
[11]
Lee, J.; Kumagai, A.; Dunphy, W.G. Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17. Mol. Cell, 2003, 11(2), 329-340.
[http://dx.doi.org/10.1016/S1097-2765(03)00045-5] [PMID: 12620222]
[12]
Clarke, C.A.L.; Bennett, L.N.; Clarke, P.R. Cleavage of claspin by caspase-7 during apoptosis inhibits the Chk1 pathway. J. Biol. Chem., 2005, 280(42), 35337-35345.
[http://dx.doi.org/10.1074/jbc.M506460200] [PMID: 16123041]
[13]
Chini, C.C.S.; Chen, J. Human claspin is required for replication checkpoint control. J. Biol. Chem., 2003, 278(32), 30057-30062.
[http://dx.doi.org/10.1074/jbc.M301136200] [PMID: 12766152]
[14]
Porterfield, V.; Khan, S.S.; Foff, E.P.; Koseoglu, M.M.; Blanco, I.K.; Jayaraman, S.; Lien, E.; McConnell, M.J.; Bloom, G.S.; Lazo, J.S.; Sharlow, E.R. A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype. Neurobiol. Aging, 2020, 90, 125-134.
[http://dx.doi.org/10.1016/j.neurobiolaging.2020.02.011] [PMID: 32184029]
[15]
Gong, Y.; Chang, L.; Viola, K.L.; Lacor, P.N.; Lambert, M.P.; Finch, C.E.; Krafft, G.A.; Klein, W.L. Alzheimer’s disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl. Acad. Sci. USA, 2003, 100(18), 10417-10422.
[http://dx.doi.org/10.1073/pnas.1834302100] [PMID: 12925731]
[16]
Giuffrida, M.L.; Caraci, F.; Pignataro, B.; Cataldo, S.; De Bona, P.; Bruno, V.; Molinaro, G.; Pappalardo, G.; Messina, A.; Palmigiano, A.; Garozzo, D.; Nicoletti, F.; Rizzarelli, E.; Copani, A. Beta-amyloid monomers are neuroprotective. J. Neurosci., 2009, 29(34), 10582-10587.
[http://dx.doi.org/10.1523/JNEUROSCI.1736-09.2009] [PMID: 19710311]
[17]
Clarke, C.A.L.; Clarke, P.R. DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system. Biochem. J., 2005, 388(2), 705-712.
[http://dx.doi.org/10.1042/BJ20041966] [PMID: 15707391]
[18]
Yang, Y.; Herrup, K. Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J. Neurosci., 2005, 25(10), 2522-2529.
[http://dx.doi.org/10.1523/JNEUROSCI.4946-04.2005] [PMID: 15758161]
[19]
Shen, X.; Chen, J.; Li, J.; Kofler, J.; Herrup, K. Neurons in vulnerable regions of the Alzheimer’s disease brain display reduced ATM signaling. eNeuro, 2016, 3(1), ENEURO.0124-15.2016.
[http://dx.doi.org/10.1523/ENEURO.0124-15.2016] [PMID: 27022623]
[20]
Blasina, A.; Price, B.D.; Turenne, G.A.; McGowan, C.H. Caffeine inhibits the checkpoint kinase ATM. Curr. Biol., 1999, 9(19), 1135-1138.
[http://dx.doi.org/10.1016/S0960-9822(99)80486-2] [PMID: 10531013]
[21]
Niida, H.; Katsuno, Y.; Banerjee, B.; Hande, M.P.; Nakanishi, M. Specific role of Chk1 phosphorylations in cell survival and checkpoint activation. Mol. Cell. Biol., 2007, 27(7), 2572-2581.
[http://dx.doi.org/10.1128/MCB.01611-06] [PMID: 17242188]
[22]
Lee, J.; Gold, D.A.; Shevchenko, A.; Shevchenko, A.; Dunphy, W.G. Roles of replication fork-interacting and Chk1-activating domains from Claspin in a DNA replication checkpoint response. Mol. Biol. Cell, 2005, 16(11), 5269-5282.
[http://dx.doi.org/10.1091/mbc.e05-07-0671] [PMID: 16148040]
[23]
Pagano, M.; Pepperkok, R.; Verde, F.; Ansorge, W.; Draetta, G. Cyclin A is required at two points in the human cell cycle. EMBO J., 1992, 11(3), 961-971.
[http://dx.doi.org/10.1002/j.1460-2075.1992.tb05135.x] [PMID: 1312467]
[24]
Geley, S.; Kramer, E.; Gieffers, C.; Gannon, J.; Peters, J.M.; Hunt, T. Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. J. Cell Biol., 2001, 153(1), 137-148.
[http://dx.doi.org/10.1083/jcb.153.1.137] [PMID: 11285280]
[25]
Xia, M.; Hyman, B.T. GROα/KC, a chemokine receptor CXCR2 ligand, can be a potent trigger for neuronal ERK1/2 and PI-3 kinase pathways and for tau hyperphosphorylation—a role in Alzheimer’s disease? J. Neuroimmunol., 2002, 122(1-2), 55-64.
[http://dx.doi.org/10.1016/S0165-5728(01)00463-5] [PMID: 11777543]
[26]
Kumagai, A.; Dunphy, W.G. Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1. Nat. Cell Biol., 2003, 5(2), 161-165.
[http://dx.doi.org/10.1038/ncb921] [PMID: 12545175]
[27]
Morris, M.C.; Depollier, J.; Mery, J.; Heitz, F.; Divita, G. A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat. Biotechnol., 2001, 19(12), 1173-1176.
[http://dx.doi.org/10.1038/nbt1201-1173] [PMID: 11731788]
[28]
Gallo, G. Making proteins into drugs: assisted delivery of proteins and peptides into living neurons. Methods Cell Biol., 2003, 71, 325-338.
[http://dx.doi.org/10.1016/S0091-679X(03)01015-X] [PMID: 12884697]
[29]
Zhang, Y.; Zhu, B.; Ma, F.; Herrup, K. Identifying a population of glial progenitors that have been mistaken for neurons in embryonic mouse cortical culture. eNeuro, 2021, 8(2), ENEURO.0388-20.2020.
[http://dx.doi.org/10.1523/ENEURO.0388-20.2020] [PMID: 33483322]
[30]
Maeda, E.; Robinson, H.P.; Kawana, A. The mechanisms of generation and propagation of synchronized bursting in developing networks of cortical neurons. J. Neurosci., 1995, 15(10), 6834-6845.
[http://dx.doi.org/10.1523/JNEUROSCI.15-10-06834.1995] [PMID: 7472441]
[31]
Klein, J.A.; Ackerman, S.L. Oxidative stress, cell cycle, and neurodegeneration. J. Clin. Invest., 2003, 111(6), 785-793.
[http://dx.doi.org/10.1172/JCI200318182] [PMID: 12639981]
[32]
Ippati, S.; Deng, Y.; van der Hoven, J.; Heu, C.; van Hummel, A.; Chua, S.W.; Paric, E.; Chan, G.; Feiten, A.; Fath, T.; Ke, Y.D.; Haass, N.K.; Ittner, L.M. Rapid initiation of cell cycle reentry processes protects neurons from amyloid-β toxicity. Proc. Natl. Acad. Sci. USA, 2021, 118(12), e2011876118.
[http://dx.doi.org/10.1073/pnas.2011876118] [PMID: 33737393]
[33]
Park, D.S.; Morris, E.J.; Greene, L.A.; Geller, H.M. G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. J. Neurosci., 1997, 17(4), 1256-1270.
[http://dx.doi.org/10.1523/JNEUROSCI.17-04-01256.1997] [PMID: 9006970]
[34]
Padmanabhan, J.; Park, D.S.; Greene, L.A.; Shelanski, M.L. Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J. Neurosci., 1999, 19(20), 8747-8756.
[http://dx.doi.org/10.1523/JNEUROSCI.19-20-08747.1999] [PMID: 10516294]
[35]
Abraham, R.T. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev., 2001, 15(17), 2177-2196.
[http://dx.doi.org/10.1101/gad.914401] [PMID: 11544175]
[36]
Choi, S.; Toledo, L.I.; Fernandez-Capetillo, O.; Bakkenist, C.J. CGK733 does not inhibit ATM or ATR kinase activity in H460 human lung cancer cells. DNA Repair (Amst.), 2011, 10(10), 1000-1001.
[http://dx.doi.org/10.1016/j.dnarep.2011.07.013] [PMID: 21865098]
[37]
Cruet-Hennequart, S.; Glynn, M.T.; Murillo, L.S.; Coyne, S.; Carty, M.P. Enhanced DNA-PK-mediated RPA2 hyperphosphorylation in DNA polymerase η-deficient human cells treated with cisplatin and oxaliplatin. DNA Repair (Amst.), 2008, 7(4), 582-596.
[http://dx.doi.org/10.1016/j.dnarep.2007.12.012] [PMID: 18289945]
[38]
Goldstein, M.; Roos, W.P.; Kaina, B. Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: Contribution of DNA replication, transcription inhibition and Chk/p53 signaling. Toxicol. Appl. Pharmacol., 2008, 229(1), 20-32.
[http://dx.doi.org/10.1016/j.taap.2008.01.001] [PMID: 18289623]
[39]
Alao, J.P.; Sunnerhagen, P. The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation. Radiat. Oncol., 2009, 4(1), 51.
[http://dx.doi.org/10.1186/1748-717X-4-51] [PMID: 19903334]
[40]
Bhattacharya, S.; Ray, R.M.; Johnson, L.R. Role of polyamines in p53-dependent apoptosis of intestinal epithelial cells. Cell. Signal., 2009, 21(4), 509-522.
[http://dx.doi.org/10.1016/j.cellsig.2008.12.003] [PMID: 19136059]
[41]
Williams, T.M.; Nyati, S.; Ross, B.D.; Rehemtulla, A. Molecular imaging of the ATM kinase activity. Int. J. Radiat. Oncol. Biol. Phys., 2013, 86(5), 969-977.
[http://dx.doi.org/10.1016/j.ijrobp.2013.04.028] [PMID: 23726004]
[42]
Zhao, H.; Piwnica-Worms, H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol. Cell. Biol., 2001, 21(13), 4129-4139.
[http://dx.doi.org/10.1128/MCB.21.13.4129-4139.2001] [PMID: 11390642]
[43]
Sørensen, C.S.; Syljuåsen, R.G.; Falck, J.; Schroeder, T.; Rönnstrand, L.; Khanna, K.K.; Zhou, B.B.; Bartek, J.; Lukas, J. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell, 2003, 3(3), 247-258.
[http://dx.doi.org/10.1016/S1535-6108(03)00048-5] [PMID: 12676583]
[44]
Kastan, M.B.; Bartek, J. Cell-cycle checkpoints and cancer. Nature, 2004, 432(7015), 316-323.
[http://dx.doi.org/10.1038/nature03097] [PMID: 15549093]
[45]
Blasius, M.; Forment, J.V.; Thakkar, N.; Wagner, S.A.; Choudhary, C.; Jackson, S.P. A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1. Genome Biol., 2011, 12(8), R78.
[http://dx.doi.org/10.1186/gb-2011-12-8-r78] [PMID: 21851590]
[46]
Rohn, T.T.; Kokoulina, P.; Eaton, C.R.; Poon, W.W. Caspase activation in transgenic mice with Alzheimer-like pathology: results from a pilot study utilizing the caspase inhibitor, Q-VD-OPh. Int. J. Clin. Exp. Med., 2009, 2(4), 300-308.
[PMID: 20057974]
[47]
Ayers, K.L.; Mirshahi, U.L.; Wardeh, A.H.; Murray, M.F.; Hao, K.; Glicksberg, B.S.; Li, S.; Carey, D.J.; Chen, R. A loss of function variant in CASP7 protects against Alzheimer’s disease in homozygous APOE ε4 allele carriers. BMC Genomics, 2016, 17(Suppl. 2), 445.
[http://dx.doi.org/10.1186/s12864-016-2725-z] [PMID: 27358062]
[48]
Barrio-Alonso, E.; Hernández-Vivanco, A.; Walton, C.C.; Perea, G.; Frade, J.M. Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons. Sci. Rep., 2018, 8(1), 14316.
[http://dx.doi.org/10.1038/s41598-018-32708-4] [PMID: 30254284]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy