CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease.
Alzheimer's disease
CDK
CDT2
Cell cycle reentry
DTL
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
21
03
2018
revised:
07
07
2018
accepted:
31
08
2018
pubmed:
16
10
2018
medline:
11
4
2020
entrez:
16
10
2018
Statut:
ppublish
Résumé
Altered cell cycle reentry has been observed in Alzheimer's disease (AD). Denticleless (DTL) was predicted as the top driver of a cell cycle subnetwork associated with AD. We systematically investigated DTL expression in AD and studied the molecular, cellular, and behavioral endophenotypes triggered by DTL overexpression. We experimentally validated that CDT2, the protein encoded by DTL, activated cyclin-dependent kinases through downregulating P21, which induced tau hyperphosphorylation and Aβ toxicity, two hallmarks of AD. We demonstrated that cyclin-dependent kinases inhibition by roscovitine not only rescued CDT2-induced cognitive defects but also reversed expression changes induced by DTL overexpression. RNA-seq data from the DTL overexpression experiments revealed the molecular mechanisms underlying CDT2 controlled cell cycle reentry in AD. These findings provide new insights into the molecular mechanisms of AD pathogenesis and thus pave a way for developing novel therapeutics for AD by targeting AD specific cell cycle networks and drivers.
Identifiants
pubmed: 30321504
pii: S1552-5260(18)33522-2
doi: 10.1016/j.jalz.2018.08.013
pmc: PMC6758558
mid: NIHMS1050452
pii:
doi:
Substances chimiques
DTL protein, human
0
Nuclear Proteins
0
tau Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
217-231Subventions
Organisme : NIA NIH HHS
ID : RF1 AG057440
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054014
Pays : United States
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG059319
Pays : United States
Organisme : NIDA NIH HHS
ID : HHSN271201300031C
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046170
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG057907
Pays : United States
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Acta Neuropathol. 1991;82(4):239-59
pubmed: 1759558
J Alzheimers Dis. 2015;43(1):57-65
pubmed: 25061053
Nature. 2017 Sep 28;549(7673):523-527
pubmed: 28959956
Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6
pubmed: 16174740
Neurobiol Aging. 2009 Apr;30(4):561-73
pubmed: 17845826
Genome Med. 2016 Nov 1;8(1):104
pubmed: 27799057
Brain. 2015 May;138(Pt 5):1327-38
pubmed: 25693589
Genet Med. 2016 May;18(5):421-30
pubmed: 26312828
J Alzheimers Dis. 2012;32(2):397-415
pubmed: 22810102
Cell. 2013 Apr 25;153(3):707-20
pubmed: 23622250
J Alzheimers Dis. 2018;62(1):175-202
pubmed: 29439343
Genes Dev. 2006 Nov 15;20(22):3117-29
pubmed: 17085480
Nat Genet. 2013 Dec;45(12):1452-8
pubmed: 24162737
Arch Neurol. 2004 Aug;61(8):1200-5
pubmed: 15313836
Genes Dev. 2012 Dec 1;26(23):2580-9
pubmed: 23152447
Alzheimers Res Ther. 2010 May 20;2(3):13
pubmed: 20497605
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Nat Cell Biol. 2004 Oct;6(10):1003-9
pubmed: 15448697
J Neurosci. 2008 Nov 26;28(48):12877-86
pubmed: 19036982
Arch Neurol. 1998 Sep;55(9):1185-91
pubmed: 9740112
Neurology. 1991 Apr;41(4):479-86
pubmed: 2011243
Pharmacol Ther. 2006 Jul;111(1):99-113
pubmed: 16274748
Cell Cycle. 2004 Mar;3(3):289-91
pubmed: 14726693
J Neurosci. 2006 Feb 1;26(5):1596-603
pubmed: 16452683
J Cell Sci. 2008 Oct 1;121(Pt 19):3271-82
pubmed: 18782865
Alzheimers Dement. 2017 Feb;13(2):152-167
pubmed: 27693185
Front Mol Neurosci. 2014 Jul 15;7:65
pubmed: 25076872
Oncogene. 1999 Feb 11;18(6):1297-302
pubmed: 10022811
J Alzheimers Dis. 2015;46(2):329-50
pubmed: 25737047
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Nat Rev Neurol. 2015 Oct;11(10):548
pubmed: 26347367
Nat Genet. 2017 Sep;49(9):1373-1384
pubmed: 28714976
Neurology. 2015 Aug 18;85(7):626-33
pubmed: 26180139
Chem Soc Rev. 2014 Oct 7;43(19):6765-813
pubmed: 24691405
J Biol Chem. 1999 Jul 2;274(27):19011-6
pubmed: 10383401
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Acta Neuropathol. 2006 Oct;112(4):389-404
pubmed: 16906426
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nature. 2004 May 27;429(6990):433-7
pubmed: 15164066
J Cell Sci. 2012 Nov 1;125(Pt 21):5124-37
pubmed: 22899714
Mol Cell. 2010 Oct 8;40(1):9-21
pubmed: 20932471
Oncoscience. 2014 Jul 23;1(7):486-503
pubmed: 25594051
Cell Cycle. 2011 Jan 15;10(2):241-9
pubmed: 21212733
Acta Neuropathol. 1996 Aug;92(2):197-201
pubmed: 8841666
Trends Neurosci. 2001 Jan;24(1):25-31
pubmed: 11163884
Cold Spring Harb Perspect Med. 2012 Mar;2(3):a006312
pubmed: 22393530
Mol Neurobiol. 2016 Sep;53(7):4328-42
pubmed: 26227906
J Alzheimers Dis. 2002 Jun;4(3):243-7
pubmed: 12226544
Mol Biol Cell. 1998 Jun;9(6):1495-512
pubmed: 9614189
Cell Cycle. 2014;13(22):3602-10
pubmed: 25483090
EMBO Rep. 2006 Nov;7(11):1134-9
pubmed: 17039252
J Cell Mol Med. 2008 Jan-Feb;12(1):38-55
pubmed: 18194444
EBioMedicine. 2016 Aug;10:85-100
pubmed: 27333051
Glia. 2010 Aug;58(10):1235-46
pubmed: 20544859
Genes Dev. 1997 Apr 1;11(7):847-62
pubmed: 9106657
Mol Cell. 2010 Oct 8;40(1):22-33
pubmed: 20932472
Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81
pubmed: 8446617
Cell. 2017 Jan 26;168(3):427-441.e21
pubmed: 28111074
Neurology. 1993 Nov;43(11):2412-4
pubmed: 8232972
Genes Dev. 2008 Sep 15;22(18):2507-19
pubmed: 18794348