Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain

Fei Liu, Inge Iqbal-Grundke, Khalid Iqbal, Yoshiya Oda, Kazuhito Tomizawa, Cheng Xin Gong

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

A disturbance of calcium homeostasis is believed to play an important role in the neurodegeneration of the brains of Alzheimer disease (AD) patients, but the molecular pathways by which it contributes to the disease are not well understood. Here we studied the activation of two major Ca2+- regulated brain proteins, calpain and calcineurin, in AD brain. We found that calpain I is activated, which in turn cleaves and activates calcineurin in AD brain. Mass spectrometric analysis indicated that the cleavage of calcineurin by calpain I is at lysine 501, a position C-terminal to the autoinhibitory domain, which produces a 57-kDa truncated form. The 57-kDa calcineurin maintains its Ca2+/calmodulin dependence of the phosphatase activity, but the phosphatase activity is remarkably activated upon truncation. The cleavage and activation of calcineurin correlate to the number of neurofibrillary tangles in human brains. These findings suggest that the overactivation of calpain I and calcineurin may mediate the role of calcium homeostatic disturbance in the neurodegeneration of AD.

Original languageEnglish
Pages (from-to)37755-37762
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number45
DOIs
Publication statusPublished - Nov 11 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Liu, F., Iqbal-Grundke, I., Iqbal, K., Oda, Y., Tomizawa, K., & Gong, C. X. (2005). Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. Journal of Biological Chemistry, 280(45), 37755-37762. https://doi.org/10.1074/jbc.M507475200