{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T07:24:52Z","timestamp":1769844292373,"version":"3.49.0"},"reference-count":57,"publisher":"American Society for Cell Biology (ASCB)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:p>Mutant Tau (MAPT) can lead to frontotemporal lobar degeneration (FTLD). Previous studies associated MAPT mutations and altered function with aneuploidy and chromosome instability in human lymphocytes and in Drosophila development. Here we examine whether FTLD-causing mutations in human MAPT induce aneuploidy and apoptosis in the mammalian brain. First, aneuploidy was found in brain cells from MAPT mutant transgenic mice expressing FTLD mutant human MAPT. Then brain neurons from mice homozygous or heterozygous for the Tau (Mapt) null allele were found to exhibit increasing levels of aneuploidy with decreasing Tau gene dosage. To determine whether aneuploidy leads to neurodegeneration in FTLD, we measured aneuploidy and apoptosis in brain cells from patients with MAPT mutations and identified both increased aneuploidy and apoptosis in the same brain neurons and glia. To determine whether there is a direct relationship between MAPT-induced aneuploidy and apoptosis, we expressed FTLD-causing mutant forms of MAPT in karyotypically normal human cells and found that they cause aneuploidy and mitotic spindle defects that then result in apoptosis. Collectively, our findings reveal a neurodegenerative pathway in FTLD-MAPT in which neurons and glia exhibit mitotic spindle abnormalities, chromosome mis-segregation, and aneuploidy, which then lead to apoptosis.<\/jats:p>","DOI":"10.1091\/mbc.e17-01-0031","type":"journal-article","created":{"date-parts":[[2017,12,27]],"date-time":"2017-12-27T17:25:18Z","timestamp":1514395518000},"page":"575-586","source":"Crossref","is-referenced-by-count":41,"title":["Mitotic defects lead to neuronal aneuploidy and apoptosis in frontotemporal lobar degeneration caused by MAPT mutations"],"prefix":"10.1091","volume":"29","author":[{"given":"Julbert","family":"Caneus","sequence":"first","affiliation":[{"name":"Department of Neurology, Rocky Mountain Alzheimer\u2019s Disease Center, University of Colorado School of Medicine, Aurora, CO 80045"},{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO 80045"},{"name":"Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoneta","family":"Granic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rocky Mountain Alzheimer\u2019s Disease Center, University of Colorado School of Medicine, Aurora, CO 80045"},{"name":"AGE Research Group, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom"},{"name":"Campus for Ageing and Vitality, Biomedical Research Building, Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom"},{"name":"NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Rademakers","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina M.","family":"Coughlan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rocky Mountain Alzheimer\u2019s Disease Center, University of Colorado School of Medicine, Aurora, CO 80045"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi J.","family":"Chial","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rocky Mountain Alzheimer\u2019s Disease Center, University of Colorado School of Medicine, Aurora, CO 80045"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huntington","family":"Potter","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rocky Mountain Alzheimer\u2019s Disease Center, University of Colorado School of Medicine, Aurora, CO 80045"},{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO 80045"},{"name":"Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1076","reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s12035-012-8262-0","volume":"46","author":"Arendt T","year":"2012","journal-title":"Mol Neurobiol"},{"key":"B2","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00401-015-1465-5","volume":"130","author":"Arendt T","year":"2015","journal-title":"Acta Neuropathol"},{"key":"B3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2353\/ajpath.2010.090955","volume":"177","author":"Arendt T","year":"2010","journal-title":"Am J Pathol"},{"key":"B4","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.3390\/ijms10041609","volume":"10","author":"Arendt T","year":"2009","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"crossref","first-page":"12564","DOI":"10.1073\/pnas.0605177103","volume":"103","author":"Bhardwaj RD","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"B6","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.neurobiolaging.2006.10.027","volume":"29","author":"Boeras DI","year":"2008","journal-title":"Neurobiol Aging"},{"key":"B7","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.4161\/cc.10.9.15478","volume":"10","author":"Borysov SI","year":"2011","journal-title":"Cell Cycle"},{"key":"B8","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1242\/dmm.022558","volume":"9","author":"Boug\u00e9 AL","year":"2016","journal-title":"Dis Model Mech"},{"key":"B9","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/978-1-4939-7280-7_16","volume-title":"Genomic Mosaicism in Neurons and Other Cell Types","volume":"131","author":"Caneus J","year":"2017"},{"key":"B10","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1242\/jcs.114.6.1179","volume":"114","author":"Dawson HN","year":"2001","journal-title":"J Cell Sci"},{"key":"B11","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1002\/glia.22837","volume":"63","author":"Duan CL","year":"2015","journal-title":"Glia"},{"key":"B12","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1038\/3305","volume":"4","author":"Eriksson PS","year":"1998","journal-title":"Nat Med"},{"key":"B13","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1111\/j.1474-9726.2012.00826.x","volume":"11","author":"Fischer HG","year":"2012","journal-title":"Aging Cell"},{"key":"B14","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1006\/nbdi.1999.0236","volume":"6","author":"Geller LN","year":"1999","journal-title":"Neurobiol Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e09-10-0850"},{"key":"B16","doi-asserted-by":"crossref","first-page":"e60718","DOI":"10.1371\/journal.pone.0060718","volume":"8","author":"Granic A","year":"2013","journal-title":"PLoS One"},{"key":"B17","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1172\/JCI200320098","volume":"112","author":"Hallbergson AF","year":"2003","journal-title":"J Clin Investig"},{"key":"B18","doi-asserted-by":"crossref","first-page":"21793","DOI":"10.1038\/srep21793","volume":"6","author":"Ibrahim S","year":"2016","journal-title":"Sci Rep"},{"key":"B19","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.nbd.2009.01.003","volume":"34","author":"Iourov IY","year":"2009","journal-title":"Neurobiol Dis"},{"key":"B20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/5056","volume":"21","author":"Jiang XR","year":"1999","journal-title":"Nat Genet"},{"key":"B21","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1750-1326-6-80","volume":"6","author":"Judge M","year":"2011","journal-title":"Mol Neurodegener"},{"key":"B22","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/cr.2008.305","volume":"19","author":"Kai Y","year":"2009","journal-title":"Cell Res"},{"key":"B23","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1007\/s00018-006-6169-5","volume":"63","author":"Kingsbury MA","year":"2006","journal-title":"Cell Mol Life Sci"},{"key":"B24","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00335-001-2128-5","volume":"13","author":"Kulnane LS","year":"2002","journal-title":"Mamm Genome"},{"key":"B25","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S0092-8674(00)80356-6","volume":"90","author":"Li J","year":"1997","journal-title":"Cell"},{"key":"B26","doi-asserted-by":"crossref","first-page":"541","DOI":"10.3233\/JAD-2009-0993","volume":"16","author":"Lopes JP","year":"2009","journal-title":"J Alzheimer\u2019s Dis"},{"key":"B27","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1097\/NEN.0000000000000241","volume":"74","author":"Lopez-Gonzalez I","year":"2015","journal-title":"J Neuropathol Exp Neurol"},{"key":"B28","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1126\/science.346.6206.237","volume":"346","author":"Magnusson JP","year":"2014","journal-title":"Science"},{"key":"B29","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.brainres.2008.04.050","volume":"1218","author":"Majd S","year":"2008","journal-title":"Brain Res"},{"key":"B30","doi-asserted-by":"crossref","first-page":"40764","DOI":"10.1038\/srep40764","volume":"7","author":"Malmanche N","year":"2017","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1126\/science.1243472","volume":"342","author":"McConnell MJ","year":"2013","journal-title":"Science"},{"key":"B32","first-page":"1933","volume":"150","author":"McShea A","year":"1997","journal-title":"Am J Pathol"},{"key":"B33","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s004390050632","volume":"101","author":"Migliore L","year":"1997","journal-title":"Hum Genet"},{"key":"B34","doi-asserted-by":"crossref","first-page":"6859","DOI":"10.1523\/JNEUROSCI.0379-07.2007","volume":"27","author":"Mosch B","year":"2007","journal-title":"J Neurosci"},{"key":"B35","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1242\/dmm.013391","volume":"7","author":"Oromendia AB","year":"2014","journal-title":"Dis Model Mech"},{"key":"B36","first-page":"1192","volume":"48","author":"Potter H","year":"1991","journal-title":"Am J Hum Genet"},{"key":"B37","doi-asserted-by":"crossref","first-page":"7","DOI":"10.2174\/156720501301151207100616","volume":"13","author":"Potter H","year":"2016","journal-title":"Curr Alzheimer Res"},{"key":"B38","first-page":"643","volume-title":"Research Advances in Alzheimer\u2019s Disease and Related Disorders","author":"Potter H","year":"1995"},{"key":"B39","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nrneurol.2012.117","volume":"8","author":"Rademakers R","year":"2012","journal-title":"Nat Rev Neurol"},{"key":"B40","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1002\/dneu.20656","volume":"68","author":"Rajendran RS","year":"2008","journal-title":"Dev Neurobiol"},{"key":"B41","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s10048-013-0380-y","volume":"15","author":"Rossi G","year":"2014","journal-title":"Neurogenetics"},{"key":"B42","doi-asserted-by":"crossref","first-page":"969","DOI":"10.3233\/JAD-2012-121633","volume":"33","author":"Rossi G","year":"2013","journal-title":"J Alzheimer\u2019s Dis"},{"key":"B43","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.4161\/cc.7.12.6012","volume":"7","author":"Rossi G","year":"2008","journal-title":"Cell Cycle"},{"key":"B44","doi-asserted-by":"crossref","first-page":"5788","DOI":"10.1523\/JNEUROSCI.0674-14.2014","volume":"34","author":"Sakamoto M","year":"2014","journal-title":"J Neurosci"},{"key":"B45","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1242\/jcs.1125880","volume":"126","author":"Seward ME","year":"2013","journal-title":"J Cell Sci"},{"key":"B46","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1242\/jcs.02907","volume":"119","author":"Sjoberg MK","year":"2006","journal-title":"J Cell Sci"},{"key":"B47","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.cell.2013.05.002","volume":"153","author":"Spalding KL","year":"2013","journal-title":"Cell"},{"key":"B48","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1212\/WNL.47.2.449","volume":"47","author":"Tatzelt J","year":"1996","journal-title":"Neurology"},{"key":"B49","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/mutage\/gem044","volume":"23","author":"Thomas P","year":"2008","journal-title":"Mutagenesis"},{"key":"B50","doi-asserted-by":"crossref","first-page":"3588","DOI":"10.1523\/JNEUROSCI.17-10-03588.1997","volume":"17","author":"Vincent I","year":"1997","journal-title":"J Neurosci"},{"key":"B51","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.neurobiolaging.2014.12.016","volume":"36","author":"Yang Y","year":"2015","journal-title":"Neurobiol Aging"},{"key":"B52","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1006\/nbdi.1997.0130","volume":"3","author":"Yehiely F","year":"1997","journal-title":"Neurobiol Dis"},{"key":"B53","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1755-8166-2-23","volume":"2","author":"Yurov YB","year":"2009","journal-title":"Mol Cytogenet"},{"key":"B54","doi-asserted-by":"crossref","first-page":"420","DOI":"10.2174\/138920210793175958","volume":"11","author":"Yurov YB","year":"2010","journal-title":"Curr Genomics"},{"key":"B55","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1755-8166-7-20","volume":"7","author":"Yurov YB","year":"2014","journal-title":"Mol Cytogenet"},{"key":"B56","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.cell.2008.01.033","volume":"132","author":"Zhao C","year":"2008","journal-title":"Cell"},{"key":"B57","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1089\/neu.2010.1579","volume":"30","author":"Zheng W","year":"2013","journal-title":"J Neurotrauma"}],"container-title":["Molecular Biology of the Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1091\/mbc.E17-01-0031","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T09:40:41Z","timestamp":1660210841000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.molbiolcell.org\/doi\/10.1091\/mbc.E17-01-0031"}},"subtitle":[],"editor":[{"given":"Erika","family":"Holzbaur","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2018,3]]},"references-count":57,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,3]]}},"alternative-id":["10.1091\/mbc.E17-01-0031"],"URL":"https:\/\/doi.org\/10.1091\/mbc.e17-01-0031","relation":{},"ISSN":["1059-1524","1939-4586"],"issn-type":[{"value":"1059-1524","type":"print"},{"value":"1939-4586","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3]]}}}