Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.
Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1-/-) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1-/- mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism.
Qin
Qingyu
Q
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific (COMP), Western University of Health Sciences, Pomona, California, United States of America.
Liao
Guanghong
G
Baudry
Michel
M
Bi
Xiaoning
X
D000818:Animals; D001369:Axons / Q000473:pathology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004795:Enzyme Stability; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis
D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D002784:Cholesterol; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein
Circ Res. 2002 Jul 26;91(2):112-9
12142343
J Neurosci. 2009 Apr 22;29(16):5183-92
19386914
Oncogene. 2002 Aug 8;21(34):5325-34
12149653
Ann Neurol. 2002 Sep;52(3):351-5
12205649
Acta Neuropathol. 1997 Aug;94(2):164-72
9255392
Oncogene. 2007 Mar 22;26(13):1920-31
16983334
Mol Cell. 2006 Feb 3;21(3):307-15
16455486
Curr Biol. 2001 Aug 21;11(16):1283-7
11525744
Eur J Neurosci. 2004 Oct;20(8):2015-21
15450080
Am J Pathol. 2005 Oct;167(4):1081-92
16192643
Thromb Haemost. 1999 Dec;82(6):1749-56
10613665
Mol Cell. 1998 Oct;2(4):405-15
9809062
J Biol Chem. 2000 Mar 24;275(12):8945-51
10722742
Acta Histochem. 1974;50(1):110-5
4140671
Exp Neurol. 2003 Dec;184(2):887-903
14769381
Acta Neuropathol. 1995;89(3):227-38
7754743
J Pathol. 2003 May;200(1):104-11
12692848
Cell Death Differ. 2007 Sep;14(9):1561-75
17627286
J Neurochem. 2002 Dec;83(5):1154-63
12437586
Brain Res. 2007 Jan 12;1128(1):175-80
17123488
J Clin Neurosci. 2009 Jul;16(7):954-9
19342246
Neuron. 2003 Mar 27;37(6):939-52
12670423
J Biol Chem. 1997 Dec 5;272(49):30766-73
9388216
Cell. 2009 Jun 26;137(7):1213-24
19563754
J Mol Biol. 2007 Jan 5;365(1):66-76
17059827
EMBO J. 2007 Aug 22;26(16):3729-36
17660744
FEBS Lett. 2009 Feb 18;583(4):615-20
19166854
Am J Pathol. 2007 Sep;171(3):962-75
17631520
Biochim Biophys Acta. 2004 Oct 11;1685(1-3):48-62
15465426
Physiol Rev. 2001 Apr;81(2):807-69
11274345
J Cell Biochem. 2003 Jan 1;88(1):76-82
12461776
Mol Pharmacol. 2000 May;57(5):976-83
10779382
Neuron. 2004 Apr 8;42(1):51-62
15066264
Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11598-603
11504915
Stem Cells. 2006 Feb;24(2):292-8
16099992
Nature. 2005 Aug 18;436(7053):1020-1024
16107849
FEBS Lett. 1998 Nov 27;440(1-2):183-7
9862451
Nat Rev Drug Discov. 2005 May;4(5):387-98
15864268
J Biol Chem. 2006 Jun 16;281(24):16814-20
16621805
Nature. 1997 May 15;387(6630):299-303
9153396
Acta Neuropathol. 1995;90(6):547-51
8615074
Exp Brain Res. 2001 Nov;141(2):218-31
11713633
J Biol Chem. 1999 Nov 5;274(45):32418-24
10542285
Nat Cell Biol. 2001 Nov;3(11):973-82
11715018
Acta Neuropathol. 1993;85(2):175-84
8382896
J Biol Chem. 2002 May 3;277(18):15600-6
11877395