Étude du rôle physiologique et pathologique de la famille miR-132/212 dans le cerveau
|Abstract:||Alzheimer's disease (AD) is the most common form of dementia in the world. At the microscopic level, two main pathological features characterize the brain of AD patients: amyloid plaques, consisting of aggregates of the Aβ (Amyloid Beta) peptide, and neurofibrillary tangles, formed by aggregates of abnormally hyperphosphorylated Tau protein. Endogenous factors that may be involved in the progression of AD include microRNAs (miRs). MiRs are small non-coding RNAs that regulate the expression of target genes at the post-transcriptional level. In particular, the miR-132/212 family is strongly downregulated in the brain of AD patients. Previous studies have shown that in the 3xTg-AD mouse model of AD, the genetic deletion of the miR-132/212 family leads to an increase in phosphorylation and aggregation of Tau protein, two mechanisms leading to the formation of neurofibrillary tangles. Apart from its role in AD, the miR-132/212 family is also involved in several neurological disorders. In particular, its level of expression is deregulated in other neurodegenerative pathologies, such as frontotemporal dementia and Parkinson's disease. It is therefore possible that the miR-132/212 family contributes to the neurodegenerative process of these pathologies. In this context, the work presented aims to study the role of the miR-132/212 family in AD and, more generally, in the brain. First of all, since the miR-132/212 family already has a known role in the formation of neurofibrillary tangles, we wanted to evaluate its involvement in the formation of the other major pathological feature of AD: the amyloid plaques. We have demonstrated that the genetic deletion of the miR-132/212 family promotes Aβ production and amyloid plaque formation in the 3xTg-AD mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Aβ metabolism, including Tau, mapk, and sirt1. Consistent with these findings, we show that the modulation of miR-132, or its target sirt1, can directly regulate Aβ production in cells. Finally, we have shown that miR-132/212 levels correlate with the amount of amyloid plaques in humans. Then, in order to elucidate the role of the miR-132/212 family in the brain, we focused on identifying targets regulated by the miR-132/212 family. In a first step, this analysis was conducted in several in vitro cell models, in which the role of miR-132, one of two components of the family, was specifically studied. In this context, we have demonstrated that the targets regulated by miR-132 are few and specific to the cell type considered. In a second step, the target identification analysis was conducted in a conditional knockout mouse model for the miR-132/212 family that we specifically generated. We have therefore characterized the molecular targets and networks modulated by the miR-132/212 family in this model. Taken together, these results suggest that i) miR-132/212 network, including Sirt1 and likely other target genes, contributes to abnormal Aβ metabolism and senile plaque deposition in AD; ii) Although miR-132 can potentially target a large number of genes simultaneously, its targeting is selective and specific to the cellular context studied. Finally, the results obtained highlight a set of new targets and signalling pathways regulated by the miR-132/212 family. In conclusion, this work contributes to the advancement of the knowledge of the physiological and pathological role of the miR-132/212 family in the brain.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||20 November 2018|
|Collection:||Thèses et mémoires|
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