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En aquesta tesi es presenten un seguit de treballs on s'estudien aspectes patogènics de diferents taupaties tals com l'estrès oxidatiu, la fosforil·lació de la proteína tau, la malfunció de la degradació proteosomal, l'acúmul de factors de transcripció en les inclusions pròpies d'aquestes malalties i el truncatge i degradació de proteïnes.L'objectiu general de la tesi has estat el d'esbrinar els components proteics que, a més de la proteína tau, es troben segrestats en les inclusions de tau en les diferents taupaties. Les diferents taupaties estudiades han estat la malaltia d'Alzheimer, la paràlisi supranuclear progressiva, la malaltia de Pick i la malaltia dels grans argiròfils.La tesi mostra com la majoria de procesos neurodegenratius estudiats són compartits per totes aquestes malalties., The aim of this thesis has been focused on the study of the common factors that may lead to neuronal degeneration in a bunch of the most frequent tauopathies. We studied oxidative stress, tau phosphorylation and truncation, glia activation, and protein trapping inside tau inclusions.We have seen that most of the neurodegenerative factors studied are quite similar among tauopathies, suggesting a common pathogenic process.

The present study investigates global transcriptional changes in frontal cortex area 8 in incidental Lewy Body disease (iLBD), Parkinson disease (PD) and Dementia with Lewy bodies (DLB). We identified different co-expressed gene sets associated with disease stages, and gene ontology categories enriched in gene modules and differentially expressed genes including modules or gene clusters correlated to iLBD comprising upregulated dynein genes and taste receptors, and down-regulated innate inflammation. Focusing on DLB, we found modules with genes significantly enriched in functions related to RNA and DNA production, mitochondria and energy metabolism, purine metabolism, chaperone and protein folding system, and synapses and neurotransmission (particularly the GABAergic system). The expression of more than fifty selected genes was assessed with RT-qPCR. Our findings provide, for the first time, evidence of molecular cortical alterations in iLBD and involvement of several key metabolic pathways and gene hubs in DLB which may underlie cognitive impairment and dementia. Key words: Lewy body diseases, dementia with Lewy bodies, cerebral cortex, transcriptome, mitochondria, synapses, neurotransmission, GABA, purine metabolism, chaperones, dynein, axonema, taste receptors.

The EBV has been linked to multiple human disease phenotypes and has been associated with cancers and other infections. Recently single gene analysis and genome-wide analysis studies have been exploited to uncover the human genetic variants that are linked with EBV diseases. It also suggested the substantial role of individual host genetics and also provided a clue in understanding the interaction between virus and human. Furthermore, the outcome of the EBV infection is a complex phenomenon governs by the variation in the genetic architecture of the viral and human genomes and/or the interacting environmental factors. Therefore, this PhD work is mainly a large-scale effort towards the understanding of the human and EBV genetic architecture to uncover the role of genetic variation in EBV associated infections, disease susceptibility, immune recognition and invasion. Our results also provide a framework on the impact of human and EBV genetic variation and their unusual interactions that highlight the human genetic influence affecting viral load reflecting the clinical behavior of EBV in LCLs and the other side viral antigenic variation modulating immune response to sustain persistence infection. This EBV-human perturbation is essential to follow-up in the context of the susceptibility of individual populations to a specific EBV associated pathology.

This thesis focuses on Human herpesvirus 4 and 6, two ubiquitous viruses with a long list of putative disease associations, ranging from malignancies such as lymphomas and carcinomas to multiple sclerosis. To date, the relatively limited genetic data on these organisms hinders the understanding of their variability and their genetic structure at a population level. We here explore wet lab techniques for the production of genetic data in a cost-effective manner in order to reach the order of magnitude that is required to unravel the genetics these viruses. After successfully identifying individuals affected by integrated chromosomally inherited human herpesvirus 6 from public datasets of sequencing data, the sequences of the infecting virus were produced by target enrichment means from the source biological sample. The testing of an in-house target enrichment protocol followed, aiming to target latently infecting virus in human saliva. While the protocol still needs optimization and the aid of alternative techniques to be suitable for cost-effective, large-scale studies, the results were very satisfactory (up to >800-fold enrichment). In parallel, long range PCRs were used to produce human herpesvirus 4 latency genes sequences from one large human healthy saliva panel including populations previously unexplored in terms of human herpesvirus 4 isolates. Thanks to the combination of wet lab techniques and data analysis, the presence of genetic patterns in the two studied viruses is emerging, with human herpesvirus 6 presenting differences in diversity between its two species, as well as signs of geographical patterns possibly in part hidden by recombination events. Different bioinformatics approaches showed instead a stronger geographical stratification in human herpesvirus 4, with regional-driven clades. This information would allow us for a correct study design when addressing the relationship between virus and disease, taking into account the natural variation of the virus, as well as help to pinpoint genetic features that might be determinant for disease triggering or development. The strong geographical patterns presented by the diseases associated to these viruses strengthen the notion of the importance of this investigation and opens an avenue of research focused on disclosing the putative relationship between viruses strain variation and the risk for these virus–associated diseases.