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Deciphering cerebellar mitochondrial alterations in Rett Syndrome

Project description

Brain mitochondria in Rett syndrome

Rett syndrome is a rare genetic disorder associated with loss of certain mental and physical abilities. It is caused by mutations in the methyl-CpG binding protein 2 (Mecp2), which binds to methylated DNA and causes transcriptional repression. The working hypothesis of the EU-funded MITORett project is that Mecp2 affects the transcription of mitochondrial genes in the cerebellum, depleting it of ATP and hence energy. Researchers will investigate mitochondrial impairment in the cerebellum in Rett syndrome and in particular which mitochondrial proteins are affected. Results will offer fundamental information on disease pathophysiology and identify novel molecular targets for therapy.

Objective

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.

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Coordinator

UNIVERSITAT AUTONOMA DE BARCELONA
Net EU contribution
€ 172 932,48
Address
Edif a campus de la uab bellaterra cerdanyola v
08193 Cerdanyola del valles
Spain

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Region
Este Cataluña Barcelona
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00