Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/7955
COMPARTIR / EXPORTAR:
SHARE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Campo DC | Valor | Lengua/Idioma |
---|---|---|
dc.contributor.advisor | Díaz-Nido, Javier | - |
dc.contributor.author | Giménez-Cassina, Alfredo | - |
dc.date.accessioned | 2008-10-22T14:12:35Z | - |
dc.date.available | 2008-10-22T14:12:35Z | - |
dc.date.issued | 2006 | - |
dc.date.submitted | 2006-07-18 | - |
dc.identifier.uri | http://hdl.handle.net/10261/7955 | - |
dc.description | Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 18-07-2006 | en_US |
dc.description.abstract | Mitochondrial dysfunction is typical of most neurodegenerative disorders and is considered a major contributor to neuronal cell degeneration although the ultimate causes for neurological diseases and mitochondrial dysfunction are diverse. In this work we have tried to counteract mitochondrial dysfunction through different approaches based upon gene transfer by HSV-1 vectors as a possible way to ameliorate neurodegeneration. First, we have established neuronal cell culture model systems to perform functional studies on neurodegeneration and neuroprotection. Thus, we have employed rotenone to elicit mitochondrial dysfunction. Rotenone triggers apoptosis in cultured mammalian neurons through inhibition of mitochondrial complex I and constitutes an interesting experimental model system to monitor the influence of mitochondrial dysfunction on neurodegeneration. Second, we have studied the effect of modulating Glycogen Synthase Kinase-3 (GSK-3) activity on rotenone toxicity, since GSK-3 is a kinase involved in the modulation of several cell processes including apoptosis. We have demonstrated that chronic, but not acute, inhibition of GSK-3 by either the expression of a dominant-negative mutant (K85R) form of GSK-3β or the treatment with chemical inhibitors of GSK-3 protects against rotenone-induced apoptosis both in human neuron-like cells and mouse brainstem primary neurons. In order to gain insight into the molecular mechanisms underlying this neuroprotective effect, we have tested for different possibilities. We have shown that GSK-3 inhibition results in increased glucose consumption by glycolysis. Moreover, neuroprotection induced by GSK-3 inhibition is abolished by blockade of glycolysis. Interestingly, chronic inhibition of GSK-3 elicited changes in subcellular localisation of some glycolytic-related proteins. After chronic inhibition of GSK-3, Hexokinase II (HKII) localizes to mitochondria, and Glucose Transporter-3 (GLUT-3) translocates to the plasma membrane. Thus, chronic inhibition of GSK-3 appears to protect neurons against mitochondrial dysfunction-induced cell death by eliciting changes in cell metabolism which include an increase in glycolytic rate to overcome the energetic depletion. Moreover, the translocation of HKII to mitochondria might additionally have an anti-apoptotic role by modulating the permeability of the mitochondrial membrane. Additionally, our results also demonstrate that chronic inhibition of GSK-3 may result in a significant increase in Brain-Derived Neurotrophic Factor (BDNF) production and subsequent secretion to the extracellular environment. Interferring with BDNF receptor TrkB signaling partially abrogated neuroprotection against rotenone-induced cell death evoked by chronic inhibition of GSK-3. Third, we have set out to develop another approach of neuroprotection against rotenone-triggered mitochondrial dysfunction by expressing frataxin, a mitochondrial protein involved in the regulation of iron metabolism and oxidative phosphorylation, among other functions. We have designed and generated frataxin genomic loci-encoding vectors and have tested for their expression in different cell types. Furthermore, we have studied frataxin expression effects on rotenone-elicited neurotoxicity, demonstrating that frataxin expression may protect neuronal cells against mitochondrial dysfunction-induced neuronal death. Finally, we have also designed viral vectors thay may report changes in frataxin promoter activity upon different conditions or throughout time. We show that erythropoietin treatment robustly increases frataxin promoter activity in human neuron-like cells. In summary, this work demonstrates the feasibility of gene transfer into neuronal cells by HSV-1 vectors to develop novel neuroprotective strategies against mitochondrial dysfunction-induced cell death. | en_US |
dc.description.sponsorship | Alfredo Giménez-Cassina ha recibido financiación del Ministerio de Educación y Ciencia dentro del programa de Formación de Personal Universitario (FPU AP2002-2446). Parte del trabajo presentado ha sido realizado durante una estancia en el laboratorio del Dr. Richard Wade-Martins, en The Wellcome Trust Centre for Human Genetics (Universidad de Oxford, Oxford, Reino Unido). El trabajo del laboratorio ha sido financiado en parte por el Ministerio de Educación y Ciencia (SAF 2003-06782) y el Ministerio de Sanidad (Red Española de Ataxias G03/056 y Fondo de Investigación Sanitaria PI051167). | en_US |
dc.format.extent | 7732191 bytes | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | spa | en_US |
dc.publisher | Universidad Autónoma de Madrid | en_US |
dc.rights | openAccess | en_US |
dc.subject | Virus del herpes simplex | en_US |
dc.title | Neuroprotección frente a la disfunción mitocondrial mediante transferencia génica con vectores herpesvirales | en_US |
dc.type | tesis doctoral | en_US |
dc.description.peerreviewed | Peer reviewed | en_US |
dc.type.coar | http://purl.org/coar/resource_type/c_db06 | es_ES |
item.openairetype | tesis doctoral | - |
item.cerifentitytype | Publications | - |
item.languageiso639-1 | es | - |
item.grantfulltext | open | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | With Fulltext | - |
Aparece en las colecciones: | (CBM) Tesis |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
Alfredo Giménez-Cassina.pdf | 7,55 MB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
Page view(s)
476
checked on 29-mar-2024
Download(s)
941
checked on 29-mar-2024
Google ScholarTM
Check
NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.