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 lysoso...

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Main Authors: Qingyu Qin, Guanghong Liao, Michel Baudry, Xiaoning Bi
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2010-04-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC2850309?pdf=render
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spelling doaj-7030b14f2a1f423c8fcbb08be4fcf5b32020-11-25T00:44:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-04-0154e999910.1371/journal.pone.0009999Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.Qingyu QinGuanghong LiaoMichel BaudryXiaoning BiPerturbation 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.http://europepmc.org/articles/PMC2850309?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Qingyu Qin
Guanghong Liao
Michel Baudry
Xiaoning Bi
spellingShingle Qingyu Qin
Guanghong Liao
Michel Baudry
Xiaoning Bi
Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.
PLoS ONE
author_facet Qingyu Qin
Guanghong Liao
Michel Baudry
Xiaoning Bi
author_sort Qingyu Qin
title Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.
title_short Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.
title_full Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.
title_fullStr Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.
title_full_unstemmed Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.
title_sort cholesterol perturbation in mice results in p53 degradation and axonal pathology through p38 mapk and mdm2 activation.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2010-04-01
description 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.
url http://europepmc.org/articles/PMC2850309?pdf=render
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AT guanghongliao cholesterolperturbationinmiceresultsinp53degradationandaxonalpathologythroughp38mapkandmdm2activation
AT michelbaudry cholesterolperturbationinmiceresultsinp53degradationandaxonalpathologythroughp38mapkandmdm2activation
AT xiaoningbi cholesterolperturbationinmiceresultsinp53degradationandaxonalpathologythroughp38mapkandmdm2activation
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