Browsing by Author "De Ferrari, GV"

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    Copy number variants in lipid metabolism genes are associated with gallstones disease in men
    (2020) Perez-Palma, E.; Bustos, B. I.; Lal, D.; Buch, S.; Azócar, L.; Toliat, M. R.; Lieb, W.; Franke, A.; Hinz, S.; Burmeister, G.; von Shonfels, W.; Schafmayer, C.; Ahnert, P.; Volzke, H.; Volker, U.; Homuth, G.; Lerch, M. M.; Puschel Illanes, Klaus; Gutiérrez Ilabaca, Rodrigo Antonio; Hampe, J.; Nurnberg, P.; Miquel P., Juan Francisco; De Ferrari, GV
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    Molecular modeling of the amyloid-β-peptide using the homology to a fragment of triosephosphate isomerase that forms amyloid in vitro
    (1999) Contreras, CF; Canales, MA; Alvarez, A; De Ferrari, GV; Inestrosa, NC
    The main component of the amyloid senile plaques found in Alzheimer's brain is the amyloid-beta-peptide (A beta), a proteolytic product of a membrane precursor protein. Previous structural studies have found different conformations for the A beta peptide depending on the solvent and pH used. In general, they have suggested an alpha-helix conformation at the N-terminal domain and a beta-sheet conformation for the C-terminal domain. The structure of the complete A beta peptide (residues 1-40) solved by NMR has revealed that only helical structure is present in A beta. However, this result cannot explain the large beta-sheet A beta aggregates known to form amyloid under physiological conditions. Therefore, we investigated the structure of A beta by molecular modeling based on extensive homology using the Smith and Waterman algorithm implemented in the MPsrch program (Blitz server). The results showed a mean value of 23 % identity with selected sequences. Since these values do not allow a clear homology to be established with a reference structure in order to perform molecular modeling studies, we searched for detailed homology, A 28% identity with an alpha/beta segment of a triosephosphate isomerase (TIM) from Culex tarralis with an unsolved three-dimensional structure was obtained. Then, multiple sequence alignment was performed considering A beta, TIM from C.tarralis and another five TIM sequences with known three-dimensional structures. We found a TIM segment with secondary structure elements in agreement with previous experimental data for A beta. Moreover, when a synthetic peptide from this TIM segment was studied in vitro, it was able to aggregate and to form amyloid fibrils, as established by Congo red binding and electron microscopy, The A beta model obtained was optimized by molecular dynamics considering ionizable side chains in order to simulate A beta in a neutral pH environment. We report here the structural implications of this study.
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    Wnt signaling involvement in β-amyloid-dependent neurodegeneration
    (2002) Inestrosa, NC; De Ferrari, GV; Garrido, JL; Alvarez, A; Olivares, GH; Barría, MI; Bronfman, M; Chacón, MA
    Alzheimer's disease (AD) is a progressive dementia paralleled by selective neuronal death, which is probably caused by the cytotoxic effects of the amyloid-p peptide (Abeta). We have observed that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and that activation of this signaling cascade prevent such cytotoxic effects. Therefore we propose that compounds which mimic this signaling cascade may be candidates for therapeutic intervention in Alzheimer's patients. (C) 2002 Elsevier Science Ltd. All rights reserved.