Deciphering cerebellar mitochondrial alterations in Rett Syndrome

Project Details


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 PVpositive
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.
Effective start/end date1/05/2118/11/23


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