Tesis doctoral de Elena Gomez De Barreda Santiago
Tau is a major neuronal microtubule-associated protein whose main known biological function is to stimulate microtubule assembly and to stabilize the microtubule network that composes the axon. Tau protein has been primarily studied due to its dysfunction in a subset of neurodegenerative disorders known as tauopathies, the most common of which is alzheimer¿s disease. These pathologies are characterized by the accumulation of abnormally hyperphosphorylated tau aggregates in the central nervous system, distributed in a pattern which correlates with the progression of dementia. It remains unclear whether the deleterious effects of tau pathologies result from a toxic gain-of-function by hyperphosphorylated and/or aggregated tau or from critical losses of normal tau function in the disease state. in order to elucidate this controversial issue, we took advantage of a transgenic mouse model in which the tau gene is disrupted. We observed that tau deficiency affected hdac6-mediated tubulin acetylation, leading to decreased acetylated-tubulin levels. In fact, we demonstrate an interaction between tau and hdac6 which we propose results in hdac6 inhibition. To further investigate tau functions, we performed a genetic array to analyze tau deficiency-derived gene expression alterations. The transcriptional analysis revealed that tau deficiency led to upregulation of the smarce1 gene, which encodes baf57 protein. Baf57 is involved in the repression of neuron specific genes, which may explain the observed delay in axonal elongation in tau deficient neurons. We also demonstrated decreased calbindin and calmodulin levels in tau deficient mice, which may correlate with reduced calcium-buffering capacity in the absence of tau. to determine the toxic role of hyperphosphorylated tau, we generated a transgenic mouse model lacking tau protein and overexpressing gsk3íY. These mice showed a delay in the progression of neurodegeneration, suggesting that tau phosphorylation results in a toxic gain-of function.
Datos académicos de la tesis doctoral «Estudio de las funciones fisiológicas y patológicas de la proteína tau mediante el uso de modelos murinos deficientes en tau«
- Título de la tesis: Estudio de las funciones fisiológicas y patológicas de la proteína tau mediante el uso de modelos murinos deficientes en tau
- Autor: Elena Gomez De Barreda Santiago
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 03/12/2010
Dirección y tribunal
- Director de la tesis
- Jesús Avila De Grado
- Tribunal
- Presidente del tribunal: pilar Gomez ramos
- Marta Nieto lópez (vocal)
- Miguel Díaz hernández (vocal)
- Ana María Mata durán (vocal)