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Deciphering cerebellar mitochondrial alterations in Rett Syndrome

Description du projet

Mitochondries cérébrales dans le syndrome de Rett

Le syndrome de Rett est une maladie génétique rare associée à la perte de certaines capacités mentales et physiques. Elle est causée par des mutations de la protéine de liaison méthyl-CpG 2 (Mecp2), qui se lie à l’ADN méthylé et provoque une répression transcriptionnelle. L’hypothèse de travail du projet MITORett, financé par l’UE, est que Mecp2 affecte la transcription des gènes mitochondriaux dans le cervelet, l’appauvrissant en ATP et donc en énergie. Les chercheurs étudieront la déficience mitochondriale dans le cervelet dans le syndrome de Rett et en particulier quelles protéines mitochondriales sont affectées. Les résultats offriront des informations fondamentales sur la physiopathologie de la maladie et identifieront de nouvelles cibles moléculaires pour le traitement.


Mutations in the X-linked gene encoding methyl-CpG binding protein 2 (Mecp2) can lead to the progressive neurodevelopmental disorder known as Rett syndrome (RTT), characterized by regression in motor, social and cognitive skills, respiratory dysrhythmias and premature lethality. Although few symptomatic treatments exist, nowadays there is still no cure for this disease.
Mecp2 acts as transcriptional regulator and its mutations directly affect the expression of targeted transcripts, including mitochondrial (MT) genes. Cerebellum is one of brain regions with larger energy requirements. 43% of its ATP consumption occurs in the molecular layer, where the high-energy demanding parvalbumin (PV)-neurons are positioned. Compelling evidence indicates aberrant MT morphology and functionality in cerebellar biopsies of RTT patients. However, the cellular substrate of these modifications remains largely unknown. In adult cerebellum Mecp2 is preferentially expressed in PV-positive cells. Hence, we hypothesize that RTT in PV-positive neurons might present a particular vulnerability to MT alterations. Thus, in this proposal I will implement a multidisciplinary approach to find candidate MT proteins differentially regulated in cerebellar PV-positive neurons associated with the MT impairments observed in RTT. To tackle this aim, I will perform proteomic, functional and metabolomic studies in MT immunoprecipitates from cerebellar PV-positive neurons of RTT mice. This project will thus give raise to: i) the first exhaustive list of MT proteins dysregulated in these cells in RTT ii) identification of functional and metabolomic impairments affecting MT functionality in PV-positive cells of RTT mice.
MITORett project will be a breakthrough in our understanding of RTT and it will provide novel insights into the pathophysiology of this disease by unveiling potential therapeutical targets to focus the forthcoming experiments dedicated on the design of more selective drugs/treatments.


Contribution nette de l'UE
€ 172 932,48
08193 Cerdanyola Del Valles

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Este Cataluña Barcelona
Type d’activité
Higher or Secondary Education Establishments
Coût total
€ 172 932,48