A central role for calcineurin in protein misfolding neurodegenerative diseases.
Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurodegenerative diseases affecting humans and animals. Dysregulation of calcium (Ca2+) and disruption of fast axonal transport (FAT) are early pathological events that lead to loss of synaptic integrity and axonal degeneration in early stages of neurodegenerative diseases. Dysregulated Ca2+in the brain is triggered by accumulation of misfolded/unfolded aggregated proteins in the endoplasmic reticulum (ER), a major Ca2+storing organelle, ultimately leading to neuronal dysfunction and apoptosis. Calcineurin (CaN), a Ca2+/calmodulin-dependent serine/threonine phosphatase, has been implicated in T cells activation through the induction of nuclear factor of activated T cells (NFAT). In addition to the involvement of several other signaling cascades, CaN has been shown to play a role in early synaptic dysfunction and neuronal death. Therefore, inhibiting hyperactivated CaN in early stages of disease might be a promising therapeutic strategy for treating patients with protein misfolding diseases. In this review, we briefly summarize the structure of CaN, inhibition mechanisms by which immunosuppressants inhibit CaN, role of CaN in maintaining neuronal and synaptic integrity and homeostasis and the role played by CaN in protein unfolding/misfolding neurodegenerative diseases.
National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
Syed Zahid Ali
SZ
Shah
National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
Tariq
T
Hussain
National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
Deming
D
Zhao
National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, 100193, China. yanglf@cau.edu.cn.
Lifeng
L
Yang
D000818:Animals; D019703:Calcineurin / Q000737:chemistry / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000378:metabolism*; D015398:Signal Transduction
D007166:Immunosuppressive Agents; D019703:Calcineurin; D002118:Calcium
Calcineurin regulation; Microglial activation; Neuroinflammation; Phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD); Tacrolimus
Int J Dev Neurosci. 2008 Apr;26(2):141-5
18093786
IUBMB Life. 2007 Jun;59(6):388-93
17613169
Prion. 2009 Oct-Dec;3(4):195-201
19887910
Curr Opin Cell Biol. 2011 Apr;23(2):223-30
21295458
Nature. 1995 Dec 7;378(6557):641-4
8524402
Neuron. 2002 Aug 15;35(4):605-23
12194863
Curr Opin Pharmacol. 2002 Aug;2(4):458-62
12127881
J Mol Neurosci. 2015 Aug;56(4):966-76
25898930
Biochem Biophys Res Commun. 2003 Nov 28;311(4):1159-71
14623302
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13522-6
12357034
Mol Brain. 2009 Oct 27;2:33
19860865
Science. 1999 Apr 9;284(5412):339-43
10195903
Curr Top Cell Regul. 2000;36:237-95
10842755
Biochemistry. 2000 Dec 19;39(50):15365-74
11112522
Nature. 1995 Aug 31;376(6543):745-53
7651533
Ageing Res Rev. 2013 Jan;12 (1):39-49
22771380
J Mol Biol. 1996 Jun 21;259(4):737-48
8683579
Neurobiol Dis. 2016 Oct;94:139-56
27334877
Cell Calcium. 2014 Sep;56(3):215-24
25108568
J Neurosci. 2001 Oct 15;21(20):7944-53
11588168
Circ Res. 2001 Jun 22;88(12):1220-2
11420294
Science. 2006 Feb 17;311(5763):1008-12
16484497
J Alzheimers Dis. 2015;45(2):561-80
25589721
J Biol Chem. 2009 May 1;284(18):12562-71
19270309
Hum Mol Genet. 2015 Jan 1;24(1):86-99
25205109
Annu Rev Biochem. 2003;72:609-42
12676795
J Mol Neurosci. 2015 Dec;57(4):529-37
26304853
J Biol Chem. 2010 Mar 5;285(10):7619-32
20032460
Cell. 1998 Jan 9;92(1):39-49
9489698
Science. 1993 Feb 5;259(5096):780-5
8430330
Annu Rev Biochem. 2007;76:367-85
17506640
Neuron. 2008 Jul 31;59(2):214-25
18667150
Hum Mol Genet. 2012 Jul 1;21(13):3025-41
22511596
Nat Commun. 2015 Dec 14;6:10119
26658127
J Neurophysiol. 2002 May;87(5):2490-504
11976386
PLoS Pathog. 2010 Oct 07;6(10):e1001138
20949081
Proc Natl Acad Sci U S A. 1988 Sep;85(18):7001-5
2842800
Acta Neuropathol. 1986;72(2):150-6
2950715
EMBO J. 1996 Dec 16;15(24):6798-809
9003755
Eur J Cell Biol. 2016 Mar-May;95(3-5):164-74
26832117
Biochem Biophys Res Commun. 2015 May 15;460(4):889-95
25839649
Nat Cell Biol. 2015 Mar;17(3):288-99
25720963
Biochem J. 2004 May 1;379(Pt 3):805-13
14741051
J Neuroinflammation. 2012 Mar 07;9:48
22397398
Science. 2002 Oct 25;298(5594):789-91
12399581
Biochem Biophys Res Commun. 1989 Sep 29;163(3):1492-7
2551293
Trends Neurosci. 2010 May;33(5):230-40
20223527
Neurosci Lett. 2004 Feb 26;357(1):73-5
15036616
Eur J Neurosci. 2000 Aug;12(8):2881-91
10971631
Neurochem Int. 2008 May;52(6):1226-33
18295934
Annu Rev Biochem. 1999;68:821-61
10872467
Adv Enzymol Relat Areas Mol Biol. 1988;61:149-200
2833077
J Neuropathol Exp Neurol. 2006 Aug;65(8):733-9
16896307
Neurobiol Dis. 2015 Apr;76:112-25
25725420
Cell. 1996 Dec 27;87(7):1203-14
8980227
J Biochem. 2002 Jan;131(1):1-15
11754729
Neurobiol Dis. 2006 Sep;23(3):669-78
16844381
Biochim Biophys Acta. 2013 Oct;1833(10):2293-301
23747341
Cell. 2001 Nov 30;107(5):617-29
11733061
Mutat Res. 2005 Jan 6;569(1-2):29-63
15603751
Trends Neurosci. 1989 Mar;12 (3):117-22
2469218
Learn Mem. 2012 Aug 16;19(9):375-84
22904368
Cell. 2001 Mar 9;104(5):675-86
11257222
Stem Cell Reports. 2015 Aug 11;5(2):157-65
26235896
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17418-23
17954914
Neuron. 1998 Apr;20(4):709-26
9581763
Cell. 2003 May 30;113(5):657-70
12787506
Physiol Rev. 2000 Oct;80(4):1483-521
11015619
Biochim Biophys Acta. 2008 Dec;1783(12):2255-61
18639592
J Neurosci Res. 2010 Oct;88(13):2923-32
20544830
Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):E3544-52
25122673
J Transplant. 2012;2012:230386
22263104
Neurobiol Dis. 2016 Jun;90:35-42
26282323
Biochim Biophys Acta. 2016 Sep;1862(9):1521-32
27212416
Neurobiol Aging. 2015 Dec;36(12 ):3239-3246
26455952
J Biol Chem. 1987 Nov 5;262(31):15062-70
2822712
Brain Res. 1986 Nov 5;397(1):161-72
3542117
Neuromolecular Med. 2013 Sep;15(3):541-8
23821337
Mol Biol Cell. 2015 Mar 15;26(6):1058-71
25609087
J Mol Neurosci. 2015 Aug;56(4):938-48
25859934
Science. 2006 Feb 17;311(5763):1012-7
16484498
J Neurosci. 2012 Feb 29;32(9):3176-92
22378890
Neuron. 1999 Oct;24(2):377-87
10571231
Curr Mol Med. 2006 Feb;6(1):37-43
16472111
Neurobiol Aging. 2013 Feb;34(2):374-86
22676853
Cell. 1995 Aug 11;82(3):507-22
7543369
J Neurochem. 2007 Oct;103(2):761-70
17666045
J Neurosci. 2007 Mar 14;27(11):2866-75
17360908
J Neurosci. 2003 Sep 3;23(22):8125-34
12954875
Arch Biochem Biophys. 2006 Feb 15;446(2):140-50
16442073
Biochim Biophys Acta. 2007 Mar;1773(3):330-41
17270291
Cell. 1998 Jan 9;92 (1):25-37
9489697
J Biol Chem. 2005 Nov 11;280(45):37755-62
16150694
Mitochondrion. 2016 Sep;30:151-61
27453331
Brain Res Bull. 2008 Jul 30;76(5):464-8
18534252
Annu Rev Biochem. 2006;75:333-66
16756495
PLoS One. 2014 Apr 21;9(4):e95471
24751678
Arch Biochem Biophys. 2000 Jul 15;379(2):337-43
10898953
Proc Natl Acad Sci U S A. 1992 May 1;89(9):3741-5
1315036
EMBO J. 2003 Oct 15;22(20):5435-45
14532116
Biol Psychiatry. 2014 Jun 15;75(12):991-8
24742621
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12037-42
12218175
Hum Mol Genet. 2014 Dec 15;23(24):6567-74
25051958
Proc Natl Acad Sci U S A. 1979 Dec;76(12):6270-3
293720
Autophagy. 2013 Sep;9(9):1386-94
23800841
Behav Brain Res. 2009 Jun 8;200(1):95-9
19162087
J Alzheimers Dis. 2015;47(2):329-33
26401556
Brain Res. 1999 Apr 10;824(2):300-3
10196463
Acta Neuropathol. 2015 Dec;130(6):829-43
26497675
Annu Rev Biochem. 2000;69:217-45
10966458
Neurosci Lett. 2011 Jan 10;487(3):260-3
20970476
Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1814-9
19717730
Neuropharmacology. 2016 Mar;102:254-65
26626486
Acta Med Okayama. 2007 Jun;61(3):123-37
17593948
J Neurophysiol. 1997 Aug;78(2):1161-5
9307144
Neuron. 2003 Apr 10;38(1):33-46
12691662
J Soc Biol. 2005;199(3):247-51
16471265
Nat Rev Neurosci. 2003 Jan;4(1):49-60
12511861
J Neurosci. 2010 Feb 17;30(7):2636-49
20164348
Cell Death Differ. 2006 Mar;13(3):385-92
16397584
Biochem Biophys Res Commun. 2003 Nov 28;311(4):1195-208
14623305
Oncogene. 2008 Oct 27;27(50):6407-18
18955969
Physiol Res. 2003;52(3):269-74
12790757
Aging Cell. 2008 Dec;7(6):824-35
18782350
Autophagy. 2015;11(7):1192-5
26043755
Nat Neurosci. 2000 Jul;3(7):661-9
10862698
J Biol Chem. 2009 May 1;284(18):11845-53
19270310
Inflamm Res. 2005 Jan;54(1):1-9
15723198