Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons

Qi Wen Fan, Wei Yu, Jian Sheng Gong, Kun Zou, Naoya Sawamura, Takao Senda, Katsuhiko Yanagisawa, Makoto Michikawa

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Microtubule-associated protein 2 (MAP2) is a neuron-specific cytoskeletal protein enriched in dendrites and cell bodies. MAP2 regulates microtubule stability in a phosphorylation-dependent manner, which has been implicated in dendrite outgrowth and branching. We have previously reported that cholesterol deficiency causes tau phosphorylation and microtubule depolymerization in axons (Fan et al. 2001). To investigate whether cholesterol also modulates microtubule stability in dendrites by modulating MAP2 phosphorylation, we examined the effect of compactin, a 3-hydroxy-3-methylglut-aryl coenzyme A (HMG-CoA) reductase inhibitor, and TU-2078 (TU), a squalene epoxidase inhibitor, on these parameters using cultured neurons. We have found that cholesterol deficiency induced by compactin and TU, inhibited dendrite outgrowth, but not of axons, and attenuated axonal branching. Dephosphorylation of MAP2 and microtubule depolymerization accompanied these alterations. The amount of protein phosphatase 2 A (PP2A) and its activity in association with microtubules were decreased, while those unbound to microtubules were increased. The synthesized ceramide levels and the total ceramide content were increased in these cholesterol-deficient neurons. These alterations caused by compactin were prevented by concurrent treatment of cultured neurons with β-migrating very-low-density lipoproteins (β-VLDL) or cholesterol. Taken together, we propose that cholesterol-deficiency causes a selective inhibition of dendrite outgrowth due to the decreased stability of microtubules as a result of inhibition of MAP2 phosphorylation.

Original languageEnglish
Pages (from-to)178-190
Number of pages13
JournalJournal of Neurochemistry
Volume80
Issue number1
DOIs
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

Dendrites
Microtubule-Associated Proteins
Microtubules
Neurons
Phosphorylation
Cholesterol
Modulation
Depolymerization
Ceramides
Squalene Monooxygenase
Protein Phosphatase 2
Cytoskeletal Proteins
VLDL Lipoproteins
VLDL Cholesterol
Coenzyme A
Oxidoreductases
Axons
Cells
Association reactions
mevastatin

Keywords

  • Axon
  • Cholesterol
  • Dendrite
  • MAP2
  • Microtubule depolymerization
  • Protein phosphatase 2A

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons. / Fan, Qi Wen; Yu, Wei; Gong, Jian Sheng; Zou, Kun; Sawamura, Naoya; Senda, Takao; Yanagisawa, Katsuhiko; Michikawa, Makoto.

In: Journal of Neurochemistry, Vol. 80, No. 1, 2002, p. 178-190.

Research output: Contribution to journalArticle

Fan, Qi Wen ; Yu, Wei ; Gong, Jian Sheng ; Zou, Kun ; Sawamura, Naoya ; Senda, Takao ; Yanagisawa, Katsuhiko ; Michikawa, Makoto. / Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons. In: Journal of Neurochemistry. 2002 ; Vol. 80, No. 1. pp. 178-190.
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