Finally, by in silico structural analysis, we propose that Ca ++ binding to hPrP 90–231 modifies amino acid orientation, in the same way induced by E200K mutation, thus suggesting a pathway for the structural alterations responsible of PrP neurotoxicity.Ĭitation: Sorrentino S, Bucciarelli T, Corsaro A, Tosatto A, Thellung S, Villa V, et al. These features, either acquired after controlled thermal denaturation or induced by D202N and E200K mutations were previously identified as responsible for hPrP 90–231 cytotoxicity. We also report that Ca ++ binding to hPrP 90–231 induces a conformational change based on an alteration of secondary structure characterized by loss of alpha-helix content causing hydrophobic amino acid exposure and proteinase K resistance. A similar correlation between increased membrane conductance and cell degeneration has been observed assaying hPrP 90–231 bearing pathogenic mutations (D202N and E200K). Furthermore we show the existence of a direct link between these two effects as demonstrated by a highly statistically significant correlation in several experimental conditions. In the present study we demonstrate that hPrP 90–231, pre-incubated with 10 mM Ca ++ and then re-suspended in physiological external solution increases not only membrane conductance but neurotoxicity as well. We previously showed that the human PrP fragment 90–231 (hPrP 90–231) increases ionic conductance across artificial lipid bilayer, in a calcium-dependent manner, producing an alteration similar to that observed for PrP Sc. PrP Sc extracted from infected Syrian hamster brains induces a considerable change in membrane ionic conductance, although the contribution of this interaction to the molecular mechanism of neurodegeneration process is still controversial. 18, 4439–4450 ( 1998).The pathological form of prion protein (PrP Sc), as other amyloidogenic proteins, causes a marked increase of membrane permeability. Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. Keller, J.N., Guo, Q., Holtsberg, F.W., Bruce-Keller, A.J. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. Calcium ionophore increases amyloid beta peptide production by cultured cells. Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: Reduced oxidative stress and preserved mitochondrial function. The presenilin 2 loop domain interacts with the μ-calpain C-terminal region. Interaction of presenilins with the filamin family of actin-binding proteins. Zhang, W., Han, S.W., McKeel, D.W., Goate, A. Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Presenilins are processed by caspase-type proteases. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Kim, T.-W., Pettingell, W.H., Jung, Y.-K., Kovacs, D.M. Identification of neuronal calcium sensor (NCS-1) possibly involved in the regulation of receptor phosphorylation. Nef, S., Fiumelli, H., de Castro, E., Raes, M.B. Molecular cloning of hippocalcin, a novel calcium-binding protein of the recoverin family exclusively expressed in hippocampus. Kobayashi, M., Takamatsu, K., Saitoh, S., Miura, M. Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase. Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. Prediction of the coding sequences of unidentified human genes. Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer's disease. Amyloid, the presenilins and Alzheimer's disease. Requirement of the familial Alzheimer's disease gene PS2 for apoptosis. Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. et al.Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. et al.Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Sherrington,R, et al.Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
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