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Epitranscriptomic Regulation in Synaptic Plasticity, Aging and Neurodegeneration

dc.contributor.advisorFischer, André Prof. Dr.
dc.contributor.authorCastro Hernández, Ricardo
dc.format.extent199 Seitende
dc.titleEpitranscriptomic Regulation in Synaptic Plasticity, Aging and Neurodegenerationde
dc.contributor.refereeFischer, André Prof. Dr.
dc.description.abstractengThe regulation of synaptic transmission and plasticity is essential for correct brain function, especially for learning and memory, while the weakening of synaptic transmission and loss of plasticity are hallmarks of the decline of cognitive function during aging or disease. Genetic, epigenetic, and, more recently, epitranscriptomic factors are known to modulate synaptic function in a context and stimulus-dependent manner, and their disfunction is linked to the onset and progression of disease or aging-associated cognitive decline. Very recently, the role of the RNA modification N6-methyladenosine (m6A) in memory function and learning has been described, with a considerable contribution of its novel role in the regulation of synaptic function and plasticity. With this in mind, my doctoral work aimed to evaluate the role that the m6A epitranscriptome could be playing in the context of both impaired and enhanced cognition and synaptic function, a relationship that is still not well understood. To this end it was first necessary to establish a protocol for the processing of samples with very limited biological material (like that of patient brain samples) that would allow me to perform unbiased sequencing-based analyses of the m6A state. Using this protocol to process and analyze samples from Alzheimer’s disease (AD) patients, I was able to compare the changes in the m6A epitranscriptome during neurodegeneration with those of a model of impaired cognition, the aged mouse brain. Then, by describing the changes in m6A in a model of enhanced cognition, like environmental enrichment, I set to find common mechanisms regulated by m6A function that could be related to cognitive function. In this work I describe the epitranscriptome of several brain regions in both mouse and human samples, finding a remarkable conservation of the populations of methylated transcripts across species, and at the same time, strong tissue specificity. During aging, a widespread decrease in the methylation levels of mRNAs involved in synaptic function across brain regions was detected, an order of magnitude larger than the equivalent changes in gene expression. This work represents the first resource describing an unbiased approach for the analysis of differential methylation in AD. These brains displayed similar decreases in methylation of several of the same genes that saw a reduction of m6A during aging in the mouse, particularly those genes involved in synaptic plasticity. Mechanistically, these changes in m6A seem to have effects on the local translation of proteins at the synapse, since one of these plasticity genes, the calcium/calmodulin-dependent protein kinase II (CaMKII), showed a strong decrease in the synthesis of its protein in synaptic compartments after the reduction of m6A levels. I also studied the epitranscriptome changes in a model where cognitive performance experiences an enhancement, rather than decline: environmental enrichment. Somewhat unexpectedly, based on the results of aging and AD, m6A marks showed a decrease following ten weeks of enrichment in the CA1. These changes also targeted transcripts coding for synaptic proteins, although with more limited enrichment. Interestingly, despite decreased methylation, the protein levels of some of these transcripts were increased in synaptic compartments. The observed changes could be driven by an increased level of the m6A reader FTO at the synapse, or through the involvement of another RNA modification, N6,2′-O-dimethyladenosine (m6Am). But more research focused on the role of m6A readers at the synapse will be needed to determine the exact mechanism of action. These results highlight the complexity and context-dependence of methylation marks and are a valuable addition to the growing evidence for the synaptic function of m6A methylation. More importantly, they represent some of the first studies that have looked for a link between the epitranscriptome landscape and how it can affect the state of synaptic transmission during cognitive enhancement and decline,de
dc.contributor.coRefereeOuteiro, Tiago Fleming Prof. Dr.
dc.subject.engm6A, RNA methylation, synaptic regulation, synaptic plasticity, aging Alzheimer's disease, environmental enrichmentde
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de
dc.notes.confirmationsentConfirmation sent 2023-02-03T15:15:01de

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