title: Truncation and activation of GSK-3β by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer's disease.
abstract: Abnormal hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase 3β (GSK-3β) is a primary tau kinase that is most implicated in tau pathology in AD. However, the exact molecular nature of GSK-3β involved in AD is unclear. In the present study, we found that GSK-3β was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Truncation of GSK-3β was positively correlated with tau hyperphosphorylation, tangles score and Braak stage in human brain. Calpain I proteolyzed GSK-3β in vitro at C-terminus, leading to an increase of its kinase activity, but keeping its characteristic to preferentially phosphorylate the protein kinase A-primed tau. Excitotoxicity induced by kainic acid (KA) caused GSK-3β truncation at C-terminus and hyperphosphorylation of tau in mouse brain. Inhibition of calpain prevented the KA-induced changes. These findings suggest that truncation of GSK-3β by Ca(2+)/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3β and consequent abnormal hyperphosphorylation of tau and neurofibrillary degeneration in AD.
authors: 1] Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China [2] Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
authors: Nana
authors: N
authors: Jin
authors: 1] Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China [2] Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
authors: Xiaomin
authors: X
authors: Yin
authors: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
authors: Dian
authors: D
authors: Yu
authors: Institute of Neurology, Department of Neurology, Hospital Affiliated to Nantong University, Nantong, Jiangsu 226001, P. R. China.
authors: Maohong
authors: M
authors: Cao
authors: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
authors: Cheng-Xin
authors: CX
authors: Gong
authors: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
authors: Khalid
authors: K
authors: Iqbal
authors: Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China.
authors: Fei
authors: F
authors: Ding
authors: Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China.
authors: Xiaosong
authors: X
authors: Gu
authors: 1] Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China [2] Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
authors: Fei
authors: F
authors: Liu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism* / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D002154:Calpain; C112682:Capn1 protein, mouse; D007608:Kainic Acid; D002118:Calcium
references: J Neurosci. 2010 Jan 20;30(3):1086-95
references: 20089917
references: J Alzheimers Dis. 2010;19(4):1221-9
references: 20308788
references: J Neurosci. 2010 Jul 7;30(27):9166-71
references: 20610750
references: Biochem Biophys Res Commun. 1989 Sep 29;163(3):1505-11
references: 2551295
references: Ann N Y Acad Sci. 1989;568:1-4
references: 2629579
references: Neurology. 1991 Apr;41(4):479-86
references: 2011243
references: J Neurosci. 2011 May 4;31(18):6627-38
references: 21543591
references: Arch Neurol. 2011 Aug;68(8):991-8
references: 21482915
references: J Biol Chem. 2012 Jun 29;287(27):22521-32
references: 22496446
references: J Biol Chem. 1992 Jan 25;267(3):1563-8
references: 1730702
references: J Neurosci. 1992 Feb;12(2):376-89
references: 1346802
references: Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32
references: 8464868
references: Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7789-93
references: 8356085
references: J Neurochem. 1999 Nov;73(5):2073-83
references: 10537067
references: J Biol Chem. 2000 Jun 2;275(22):17166-72
references: 10748088
references: Nature. 2000 May 18;405(6784):360-4
references: 10830966
references: J Biol Chem. 2000 Dec 29;275(52):41340-9
references: 11007782
references: J Biol Chem. 2001 Jan 5;276(1):251-60
references: 11013232
references: EMBO J. 2001 Jan 15;20(1-2):27-39
references: 11226152
references: J Biol Chem. 2001 Mar 9;276(10):7366-75
references: 11104755
references: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8
references: 11381127
references: Science. 2001 Aug 24;293(5534):1491-5
references: 11520988
references: J Neurochem. 2002 Jun;81(5):1073-83
references: 12065620
references: FEBS Lett. 2002 Oct 23;530(1-3):209-14
references: 12387894
references: Nat Rev Neurosci. 2002 Nov;3(11):862-72
references: 12415294
references: N Engl J Med. 2003 Apr 3;348(14):1333-41
references: 12672860
references: Proc Natl Acad Sci U S A. 2003 May 27;100(11):6370-5
references: 12750461
references: Physiol Rev. 2003 Jul;83(3):731-801
references: 12843408
references: J Alzheimers Dis. 2003 Aug;5(4):301-8
references: 14624025
references: J Biol Chem. 2004 Jan 30;279(5):3801-6
references: 14602710
references: J Biol Chem. 2004 Feb 6;279(6):4929-40
references: 14627704
references: Am J Pathol. 2004 Sep;165(3):795-805
references: 15331404
references: J Biol Chem. 1986 May 5;261(13):6084-9
references: 3084478
references: Proc Natl Acad Sci U S A. 1986 Jun;83(11):4044-8
references: 2424016
references: Acta Neuropathol. 1991;82(4):239-59
references: 1759558
references: Biochem J. 1993 Nov 15;296 ( Pt 1):15-9
references: 8250835
references: Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5562-6
references: 8202528
references: Curr Biol. 1994 Dec 1;4(12):1077-86
references: 7704571
references: J Cell Physiol. 1995 Jun;163(3):493-501
references: 7539811
references: Eur J Biochem. 1995 Oct 1;233(1):9-17
references: 7588778
references: Nat Med. 1996 Jul;2(7):783-7
references: 8673924
references: Neurosci Lett. 1996 Jan 12;203(1):33-6
references: 8742040
references: J Neurochem. 1996 Aug;67(2):699-707
references: 8764598
references: J Cell Sci. 1996 Jun;109 ( Pt 6):1537-43
references: 8799840
references: J Neurosci Res. 1997 May 1;48(3):181-91
references: 9160241
references: Neurobiol Aging. 1997 Jul-Aug;18(4):351-7
references: 9330961
references: Annu Rev Neurosci. 1998;21:347-75
references: 9530500
references: FEBS Lett. 1998 Sep 25;436(1):28-34
references: 9771888
references: Proc Natl Acad Sci U S A. 2005 May 10;102(19):6990-5
references: 15867159
references: J Biol Chem. 2005 Nov 11;280(45):37755-62
references: 16150694
references: Ann Neurol. 2005 Dec;58(6):829-39
references: 16315267
references: Acta Neuropathol. 2005 Dec;110(6):547-56
references: 16228182
references: Nat Med. 2006 Jul;12(7):780-4
references: 16829947
references: Neurobiol Aging. 2006 Sep;27(9):1258-68
references: 16054268
references: ChemMedChem. 2006 Feb;1(2):256-66
references: 16892358
references: FEBS Lett. 2006 Nov 13;580(26):6269-74
references: 17078951
references: J Neurochem. 2006 Dec;99(6):1445-55
references: 17059563
references: J Neurosci. 2007 Feb 21;27(8):1981-91
references: 17314294
references: Am J Pathol. 2007 May;170(5):1669-75
references: 17456772
references: J Biol Chem. 2007 Aug 3;282(31):22406-13
references: 17569662
references: J Neurochem. 2007 Dec;103(6):2462-70
references: 17908236
references: Eur J Neurosci. 2007 Dec;26(12):3429-36
references: 18052981
references: Neurosci Lett. 2008 Mar 21;434(1):93-8
references: 18289787
references: FASEB J. 2008 Sep;22(9):3224-33
references: 18509201
references: Trends Neurosci. 2008 Sep;31(9):454-63
references: 18675468
references: J Neurosci. 2009 Jul 22;29(29):9330-43
references: 19625523
references: Neurobiol Dis. 2009 Sep;35(3):359-67
references: 19523516