MITORett · Deciphering cerebellar mitochondrial alterations in Rett Syndrome

Deciphering cerebellar mitochondrial alterations in Rett Syndrome

Rett syndrome is a progressive neurodegenerative disorder caused by mutations in the Mecp2 gene and affecting primarily women. Although individuals with Rett syndrome initially exhibit typical development during the initial years of life, they subsequently experience a rapid regression, losing language and motor coordination skills. This regression is accompanied by the development of cognitive deficits, stereotyped hand movements, ataxia, seizures, respiratory dysrhythmias, and alterations in social behavior. Despite available treatments to alleviate symptoms, there's still no cure for Rett syndrome disease. The MECP2 protein plays a pivotal role in regulating gene expression, and mutations in MECP2 directly impact its target genes. Animal models, particularly those focusing on specific brain cell types, have contributed valuable insights into the underlying mechanisms of the syndrome. In a study involving a mouse model of Rett Syndrome where Mecp2 was suppressed in a particular sub-type of inhibitory neurons known as Parvalbumin-neurons, motor impairments, spasticity, social and memory deficits, and premature lethality were observed in Rett Syndrome mice. Parvalbumin-neurons, characterized by substantial energy requirements, are distributed across various brain regions, including the cerebellum, a region with significant energy demands and a substantial population of Parvalbumin-neurons. Mitochondria, essential cellular organelles, play a pivotal role in energy production. Previous studies have reported mitochondrial alterations in individuals with Rett Syndrome, despite that the specific regional and cellular identity of these alterations remain unexplored. This project hypothesizes that cerebellar Parvalbumin-positive neurons, with their pronounced energy requirements, may be particularly vulnerable to mitochondrial alterations in Rett Syndrome. To address this hypothesis, the research proposal suggests analyzing whether the expression of mitochondrial proteins in cerebellar Parvalbumin-neurons is affected by the Mecp2 mutation. Additionally, an examination of potential modifications in mitochondrial functionality in Rett Syndrome mice is proposed. To accomplish this, histological and transcriptomic experiments have been conducted in a mouse model with Mecp2 suppression in Parvalbumin-neurons. Ongoing proteomic and functional experiments that are under compilation will complement this work.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз