Site-specific Phosphorylation of Tau Accompanied by Activation of Mitogen-activated Protein Kinase (MAPK) in Brains of Niemann-Pick Type C Mice

Naoya Sawamura, Jian Sheng Gong, William S. Garver, Randall A. Heidenreich, Haruaki Ninomiya, Kousaku Ohno, Katsuhiko Yanagisawa, Makoto Michikawa

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Niemann-Pick type C (NPC) disease is characterized by an accumulation of cholesterol in most tissues and progressive neurodegeneration with the formation of neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF), a major component of which is the hyperphosphorylated tau. In this study we used NPC heterozygous and NPC homozygous mouse brains to investigate the molecular mechanism responsible for tauopathy in NPC. Immunoblot analysis using anti-tau antibodies (Tau-1, PHF-1, AT-180, and AT-100) revealed site-specific phosphorylation of tau at Ser-396 and Ser-404 in the brains of NPC homozygous mice. Mitogen-activated protein kinase, a potential serine kinase known to phosphorylate tau, was activated, whereas other serine kinases such as glycogen synthase kinase-3β and cyclin-dependent kinase 5 were inactive. Morphological examination demonstrated that a number of neurons, the perikarya of which strongly immunostained with PHF-1, exhibited polymorphorous cytoplasmic inclusion bodies and multi-concentric lamellar-like bodies. Importantly, the accumulation of intracellular cholesterol in NPC mouse brains was determined to be a function of age. From these results we conclude that abnormal cholesterol metabolism due to the genetic mutation in NPC1 may be responsible for activation of the mitogen-activated protein kinase-signaling pathway and site-specific phosphorylation of tau in vivo, leading to tauopathy in NPC.

Original languageEnglish
Pages (from-to)10314-10319
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number13
DOIs
Publication statusPublished - 2001 Mar 30
Externally publishedYes

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Phosphorylation
Mitogen-Activated Protein Kinases
Tauopathies
Brain
Neurofibrillary Tangles
Protein-Serine-Threonine Kinases
Chemical activation
Inclusion Bodies
Cholesterol
Type C Niemann-Pick Disease
Cyclin-Dependent Kinase 5
Glycogen Synthase Kinase 3
Metabolism
Neurons
Anti-Idiotypic Antibodies
Tissue
Mutation
Antibodies

ASJC Scopus subject areas

  • Biochemistry

Cite this

Site-specific Phosphorylation of Tau Accompanied by Activation of Mitogen-activated Protein Kinase (MAPK) in Brains of Niemann-Pick Type C Mice. / Sawamura, Naoya; Gong, Jian Sheng; Garver, William S.; Heidenreich, Randall A.; Ninomiya, Haruaki; Ohno, Kousaku; Yanagisawa, Katsuhiko; Michikawa, Makoto.

In: Journal of Biological Chemistry, Vol. 276, No. 13, 30.03.2001, p. 10314-10319.

Research output: Contribution to journalArticle

Sawamura, Naoya ; Gong, Jian Sheng ; Garver, William S. ; Heidenreich, Randall A. ; Ninomiya, Haruaki ; Ohno, Kousaku ; Yanagisawa, Katsuhiko ; Michikawa, Makoto. / Site-specific Phosphorylation of Tau Accompanied by Activation of Mitogen-activated Protein Kinase (MAPK) in Brains of Niemann-Pick Type C Mice. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 13. pp. 10314-10319.
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abstract = "Niemann-Pick type C (NPC) disease is characterized by an accumulation of cholesterol in most tissues and progressive neurodegeneration with the formation of neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF), a major component of which is the hyperphosphorylated tau. In this study we used NPC heterozygous and NPC homozygous mouse brains to investigate the molecular mechanism responsible for tauopathy in NPC. Immunoblot analysis using anti-tau antibodies (Tau-1, PHF-1, AT-180, and AT-100) revealed site-specific phosphorylation of tau at Ser-396 and Ser-404 in the brains of NPC homozygous mice. Mitogen-activated protein kinase, a potential serine kinase known to phosphorylate tau, was activated, whereas other serine kinases such as glycogen synthase kinase-3β and cyclin-dependent kinase 5 were inactive. Morphological examination demonstrated that a number of neurons, the perikarya of which strongly immunostained with PHF-1, exhibited polymorphorous cytoplasmic inclusion bodies and multi-concentric lamellar-like bodies. Importantly, the accumulation of intracellular cholesterol in NPC mouse brains was determined to be a function of age. From these results we conclude that abnormal cholesterol metabolism due to the genetic mutation in NPC1 may be responsible for activation of the mitogen-activated protein kinase-signaling pathway and site-specific phosphorylation of tau in vivo, leading to tauopathy in NPC.",
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