Tesis doctoral de Soraya Santana Martinez
Mounting evidence suggests that herpes simplex virus type 1 (hsv-1) is involved in the pathogenesis of alzheimer¿s disease (ad). Hsv-1 is a neurotropic virus that remains latent in host neurons and it is the most common cause of sporadic viral encephalitis. Epidemiological analyses have shown that hsv-1 is a risk factor for ad in people with at least one type 4 allele of the apolipoprotein e gene. Recent studies have also suggested that hsv-1 contributes to the appearance of the biochemical anomalies characteristic of ad brains. In addition, autophagic activity appears to be reduced with ageing, and the final stages of autophagy in neurodegenerative process appear to be impaired. Autophagy is a homeostatic process involved in the turnover or elimination of cytoplasmic components, damaged organelles and protein aggregates via a lysosomal degradation mechanism. Hsv-1 can modulate the autophagic process through a mechanism mediated by the viral protein icp34.5. In this thesis, we report that hsv-1 induces a strong increase in gfp-lc3 and endogenous lc3 lipidation, and triggers the accumulation of intracellular autophagic compartments, mainly autophagosomes, without enhancing autophagic long-lived protein degradation in the late stages of infection. This effect is mediated by blocking the fusion of autophagosomes with lysosomes. Moreover, hsv-1 provokes the strong intracellular accumulation of both the main species of íY-amyloid (aíY) in the autophagic compartments and that it is associated with a marked inhibition of aíY secretion. However, autophagy is not functionally involved in the aíY accumulation induced by hsv-1 infection. Autophagosomes containing aíY failed to fuse with lysosomes in hsv-1 infected cells, indicating the impaired degradation of aíY localized in the autophagic vesicles. In addition, hsv-1 infection was associated with the increase of gamma-secretase activity and the inhibition of the non-amyloidogenic pathway of app processing. Finally, our results indicate that oxidative stress, one of the earliest events in ad pathogenesis, exacerbates the effects of hsv-1 on app processing and accumulation of autophagosomes. Taken together, these data suggest that hsv-1 infection deeply controls the autophagic pathway and app processing. The dysregulation of both processes induced by hsv-1 could contribute to the accumulation of aíY characteristic of ad.
Datos académicos de la tesis doctoral «Efectos de la infeccion con el virus herpes simplex tipo 1 en celulas neuronales y su relacion con la enfermedad de alzheimer«
- Título de la tesis: Efectos de la infeccion con el virus herpes simplex tipo 1 en celulas neuronales y su relacion con la enfermedad de alzheimer
- Autor: Soraya Santana Martinez
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 28/04/2010
Dirección y tribunal
- Director de la tesis
- Jesús Aldudo Soto
- Tribunal
- Presidente del tribunal: José javier Lucas lozano
- eva Carro díaz (vocal)
- María trinidad Herrero ezquerro (vocal)
- Miguel Calero lara (vocal)