Please use this identifier to cite or link to this item:
logo share SHARE BASE
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE

Estudios sobre la fosforilación y agregación de la proteína tau y su posible relación con la enfermedad de Alzheimer

AuthorsSanta María, Ismael CSIC
AdvisorMoreno Muñoz, Francisco José; Hernández Pérez, Félix
KeywordsEnfermedad de Alzheimer
Fosforilación de proteínas
Issue Date2008
PublisherUniversidad Autónoma de Madrid
AbstractThe appearance of aberrant structures, in Alzheimer disease, like neurofibrillary tangles, senile plaques or Hirano bodies has been described. Although the etiology of Alzheimer’s disease is still incompletely understood it is thought that oxidative stress could play an important role in the onset and the progression of the disease. In addition to the oxidative stress promoted by amyloid β aggregates, mitochondria generate most of the reactive oxygen species produced during disease. Coenzyme Q is an important cofactor of mitochondrial bioenergetics and it has been directly involved, together with secondary metabolites obtained from xenobiotics metabolism, with aging related energetic changes. Quinones represent a class of intermediary metabolites that may produce cellular damage. The toxicity of quinones may take place through arylation reactions of important biomolecules like DNA or proteins. Alternatively, quinones, depending on the redox state, could exert prooxidant or antioxidant effects. On the other hand, it has been described that compounds like 4-hydroxi-2-nonenal, which are products of lipid peroxidation, could favour the assembly of aberrant structures like paired helical filaments present in neurofibrillary tangles. Compounds that are produced as a consequence of oxidative stress also may affect other microtubular proteins like tubulin. Since it has been described the connection between oxidative stress and the assembly of aberrant structures, we wanted to study if quinones also could have the same effect on protein tau aberrant assembly and Hirano bodies formation. First, we have identified the presence of quinones both in paired helical filaments and Hirano bodies. Once we have stated quinones may be involved in the formation of these aberrant structures that appear in Alzheimer disease, we have studied the effect of this molecules on tau polymerization or aggregation both in vitro and in cell cultures. On the other hand we have also tested if quinones could facilitate the formation of Hirano-like bodies in vitro. Additionally, since microtubule network has been found affected in the onset and progression of Alzheimer disease we have studied the effect of quinones on microtubule network in cell cultures. We have observed that quinones could react with tubulin hampering microtubule polimerization. Thus, we propose that quinones produced by oxidative stress generated during Alzheimer disease, favour polymerization or aggregation of tau protein and prevent microtubule polymerization causing both disturbance on axonal transport and synaptic dysfunction. Other well known inducers of tau aggregation are high molecular weight sulphated glycosaminoglycans, which also are known to favour the Aβ peptide aggregation. Nowadays pharmaceutical companies are developing low molecular weight structural analogs of sulphated glycosaminoglycans to avoid the formation of Aβ aggregates. One of these compounds is Tramiprosate (3-APS). This compound is able to interact with Aβ peptide preventing its aggregation but until now, any research group was studied the effect of this small molecule on tau aggregation. Thus, and finally we have analyzed this interaction demonstrating that 3-APS facilitates aggregation of tau. In this way, also we have tested he effect of its structural analog, taurine, which may promote tau aggregation but in less extent. In summary, our work demonstrates that tau protein modifications provoked by oxidative stress could explain, in part, what is occurring in Alzheimer disease and other tauopathies: its hyperphosphorylation and aggregation
DescriptionTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 28-03-2008
Appears in Collections:(CBM) Tesis

Files in This Item:
File Description SizeFormat
Ismael Santa María Pérez.pdf22,87 MBAdobe PDFThumbnail
Show full item record
Review this work

Page view(s)

checked on May 24, 2022


checked on May 24, 2022

Google ScholarTM


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.