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 language | English |
|---|---|
| Pages (from-to) | 37755-37762 |
| Number of pages | 8 |
| Journal | Journal of Biological Chemistry |
| Volume | 280 |
| Issue number | 45 |
| DOIs | |
| Publication status | Published - Nov 11 2005 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
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Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. / Liu, Fei; Iqbal-Grundke, Inge; Iqbal, Khalid; Oda, Yoshiya; Tomizawa, Kazuhito; Gong, Cheng Xin.
In: Journal of Biological Chemistry, Vol. 280, No. 45, 11.11.2005, p. 37755-37762.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain
AU - Liu, Fei
AU - Iqbal-Grundke, Inge
AU - Iqbal, Khalid
AU - Oda, Yoshiya
AU - Tomizawa, Kazuhito
AU - Gong, Cheng Xin
PY - 2005/11/11
Y1 - 2005/11/11
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=27844553889&partnerID=8YFLogxK
U2 - 10.1074/jbc.M507475200
DO - 10.1074/jbc.M507475200
M3 - Article
C2 - 16150694
AN - SCOPUS:27844553889
VL - 280
SP - 37755
EP - 37762
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 45
ER -