Régulation de la diacylglycérol kinase kappa (DGKk) par FMRP et sa dérégulation dans le syndrome de l’X Fragile
Year: 2024
Type: dissertation
Abstract: Fragile X syndrome (FXS) is the main cause of inherited intellectual disability and autism. FXS results from the lack of FMRP that leads to aberrant neuronal protein synthesis associated with neurological alterations. The team found that diacylglycerol kinase kappa (DGKκ) is a primary mRNA target of FMRP in cortical neurons. DGKκ is an enzyme regulating lipid signaling whose downregulation upon loss of FMRP could account for several main alterations observed in FXS. We demonstrated that the reexpression of DGKκ into the brains of Fmr1-KO mice using adeno-associated viral vectors provides long-term correction of the core FXS phenotypes. We identified the binding site of FMRP on DGKκ mRNA and underscored the contribution of m6A RNA modifications in FMRP binding to DGKκ mRNA and its translational control. Additionally, we evidenced the contribution of DGKκ to neurological functions by the characterization of the Dgkk-KO mouse model that recapitulates hallmarks of FXS phenotypes. Overall, this study demonstrates the pivotal role of DGKκ in brain functions and its contributions to FXS, and proposes a novel model by which FMRP controls the expression of an mRNA target.
Source: theses.fr (ABES)
Author: Çakil, Oktay
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7094520437
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