title: Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.
abstract: Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
authors: 1] INSERM U744, Université Lille Nord de France, Institut pasteur de Lille, Lille, France [2] Université Lille Nord de France, Institut pasteur de Lille, Lille, France [3] Université Lille-Nord de France, Institut pasteur de Lille, Lille, France.
authors: J
authors: J
authors: Chapuis
authors: F
authors: F
authors: Hansmannel
authors: M
authors: M
authors: Gistelinck
authors: A
authors: A
authors: Mounier
authors: C
authors: C
authors: Van Cauwenberghe
authors: K V
authors: KV
authors: Kolen
authors: F
authors: F
authors: Geller
authors: Y
authors: Y
authors: Sottejeau
authors: D
authors: D
authors: Harold
authors: P
authors: P
authors: Dourlen
authors: B
authors: B
authors: Grenier-Boley
authors: Y
authors: Y
authors: Kamatani
authors: B
authors: B
authors: Delepine
authors: F
authors: F
authors: Demiautte
authors: D
authors: D
authors: Zelenika
authors: N
authors: N
authors: Zommer
authors: M
authors: M
authors: Hamdane
authors: C
authors: C
authors: Bellenguez
authors: J-F
authors: JF
authors: Dartigues
authors: J-J
authors: JJ
authors: Hauw
authors: F
authors: F
authors: Letronne
authors: A-M
authors: AM
authors: Ayral
authors: K
authors: K
authors: Sleegers
authors: A
authors: A
authors: Schellens
authors: L V
authors: LV
authors: Broeck
authors: S
authors: S
authors: Engelborghs
authors: P P
authors: PP
authors: De Deyn
authors: R
authors: R
authors: Vandenberghe
authors: M
authors: M
authors: O'Donovan
authors: M
authors: M
authors: Owen
authors: J
authors: J
authors: Epelbaum
authors: M
authors: M
authors: Mercken
authors: E
authors: E
authors: Karran
authors: M
authors: M
authors: Bantscheff
authors: G
authors: G
authors: Drewes
authors: G
authors: G
authors: Joberty
authors: D
authors: D
authors: Campion
authors: J-N
authors: JN
authors: Octave
authors: C
authors: C
authors: Berr
authors: M
authors: M
authors: Lathrop
authors: P
authors: P
authors: Callaerts
authors: D
authors: D
authors: Mann
authors: J
authors: J
authors: Williams
authors: L
authors: L
authors: Buée
authors: I
authors: I
authors: Dewachter
authors: C
authors: C
authors: Van Broeckhoven
authors: P
authors: P
authors: Amouyel
authors: D
authors: D
authors: Moechars
authors: B
authors: B
authors: Dermaut
authors: J-C
authors: JC
authors: Lambert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D058068:Endophenotypes; D015870:Gene Expression / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051379:Mice; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D058225:Plaque, Amyloid / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013574:Synaptosomes / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D002352:Carrier Proteins; D029721:Drosophila Proteins; C054369:MAPT protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C407043:bicoid interacting protein 1, Drosophila; D016875:tau Proteins
references: Biochim Biophys Acta. 2006 Aug;1761(8):897-912
references: 16938488
references: J Neurosci. 2010 Jan 13;30(2):464-77
references: 20071510
references: Lancet. 2011 Feb 19;377(9766):641-9
references: 21292315
references: Traffic. 2001 Nov;2(11):839-50
references: 11733051
references: J Mol Biol. 2005 Aug 5;351(1):182-94
references: 15992821
references: JAMA. 2010 May 12;303(18):1832-40
references: 20460622
references: Nat Genet. 2009 Oct;41(10):1094-9
references: 19734903
references: PLoS Genet. 2012;8(4):e1002595
references: 22496665
references: J Neurol Neurosurg Psychiatry. 2005 Jul;76(7):928-33
references: 15965197
references: Nat Genet. 2009 Oct;41(10):1088-93
references: 19734902
references: Eur J Cell Biol. 2009 Feb;88(2):91-102
references: 19004523
references: Neurobiol Aging. 2001 Mar-Apr;22(2):227-35
references: 11182472
references: Nat Genet. 2011 Jun 19;43(7):699-705
references: 21685912
references: Mol Psychiatry. 2013 Apr;18(4):461-70
references: 22430674
references: Nat Genet. 2010 Mar;42(3):234-9
references: 20154673
references: J Neurochem. 1984 Oct;43(4):1114-23
references: 6088694
references: Biochem Biophys Res Commun. 2010 Jan 1;391(1):510-6
references: 19931224
references: Biochem Biophys Res Commun. 2005 Oct 21;336(2):572-8
references: 16139795
references: J Cell Biol. 1997 Jun 16;137(6):1355-67
references: 9182667
references: PLoS Genet. 2010 Apr 01;6(4):e1000895
references: 20369022
references: Neuroscience. 2005;132(1):123-35
references: 15780472
references: Mol Psychiatry. 2009 Nov;14(11):1004-16
references: 19204726
references: Genes Dev. 2001 Nov 15;15(22):2967-79
references: 11711432