Participación de faim-l en la enfermedad de Alzheimer y otras tauopatías: descifrando el papel de faim-l en la ubiquitinación de TAU, El mantenimiento sináptico y la memoria durante el desarrollo de la patología de TAU

• Autores: Raquel Badillos Rodríguez
• Directores de la Tesis: Joan Xavier Comella i Carnicé (dir. tes.), Montserrat Solé Piñol (codir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2023
• Idioma: español
• Tribunal Calificador de la Tesis: Antonia Gutiérrez Pérez (presid.), Elisenda Sanz Iglesias (secret.), Marta Pascual (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Autónoma de Barcelona
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Alzheimers disease (AD) is the most prevalent type of dementia worldwide and one of the most relevant disorders among a group of neurodegenerative diseases named tauopathies. These diseases are characterized by the aberrant modification and progressive accumulation of the protein tau. Tau protein, initially described to stabilize microtubules, participates in other multiple cellular processes, including DNA repair, synaptic plasticity, and mitochondrial maintenance. Consequently, it is an essential protein for cellular homeostasis but also can become the trigger of the neuronal failure and loss associated to this type of diseases, especially to AD. Our group has been centred in the study of the neuro-specific long isoform of the Fas Apoptotic Inhibitory Molecule, FAIM-L. Furthermore, we have been pioneers in describing unique roles of this protein through its capacity to inhibit certain non-apoptotic functions of caspase-3. Importantly, our group was the first in linking FAIM-L to neurodegeneration by finding it decreased in both AD patients and in a mouse model of the disease. Since FAIM-L is implicated in the correct control of apoptosis and synaptic processes, we propose that its loss may be promoting the progression of AD. To explore this hypothesis, we aimed to elucidate the molecular mechanisms involved in FAIM-L reduction and the consequences of its decrease. Additionally, we have analysed the functional implications of FAIM-L levels restoration using in vivo adeno-associated viral injections. Therefore, we would like to propose FAIM-L as a potential therapeutical target for AD.

    Importantly, we found that the reduction of FAIM-L was directly linked to tau pathology and was not directly dependent on amyloid pathology. Also, by using the Frontotemporal Dementia linked to Parkinsonism (FTDP-17) mouse model, the PS19 mice, we proved that this decrease occurs before other pathological alterations such as synaptic impairment and reactive gliosis and that it is associated to a decrease in XIAP levels and an anomalous increase in global ubiquitination. This early reduction of FAIM-L in the course of the pathology offers a new therapeutic window that is clearly supported by the results obtained after FAIM-L modulation in vivo. Our novel findings show that FAIM-L expression restoration in the hippocampus of the PS19 mice completely avoided dendritic spine loss and helped maintaining synaptic integrity by preventing PSD95 and mGluR2 losing the postsynaptic compartment. Consequently, FAIM-L overexpression prevented brain atrophy as well as learning and memory impairment in our model. The relationship between FAIM-L and tau pathology is reinforced by our in vitro experiments in which we were able to describe, for the first time, that FAIM-L reduction depends on the increase in phosphorylation levels of tau and, indeed, to report a functional connection between these two proteins. In this work, we also demonstrate that FAIM-L interacts with both wild-type and mutant tau isoforms and avoids its ubiquitination.

    In summary, our results confirm FAIM-L implication in AD but also settle it an essential element for neuronal survival, synaptic maintenance and cognition. Also, these findings allow to suggest that FAIM-L confers early protection from tau-associated alterations and place it as a potential target for therapeutic approaches, not only for AD but possibly for FTDP-17 and the rest of tauopathies.