title: Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain.
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 Ca(2+)-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 Ca(2+)/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.
authors.affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, USA. feiliu63@hotmail.com
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Oda
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tomizawa
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D001921:Brain / Q000201:enzymology*; D019703:Calcineurin / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling; D002154:Calpain / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data
chemical_list: D019703:Calcineurin; D002154:Calpain