A structural, functional and behavioral study on the epigenetic control by histone deacetylases (HDAC) in a mouse model of Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a lethal X-linked disease characterized by muscular wasting and neurological disturbances due to lack of dystrophin (Dp427), a cytoskeletal protein expressed in muscle and selected brain regions (i.e. hippocampus, cerebellum, prefrontal cortex). Dp427 binds to the Dystrophin Glycoprotein Complex (DGC) that spans the plasma membrane and is implicated in maintaining structural and functional properties of cellular sub-domains. The DGC also binds to several other molecules, some of which drive important intracellular signaling pathways. Among them is the neuronal nitric oxide synthase (nNOS), which synthesizes nitric oxide (NO), a signaling molecule involved in several physiological and pathological events: i.e. neurogenesis, hippocampal long-term potentiation, neurodegeneration, neuronal survival and differentiation. NO signaling implies nitrosylation of target proteins, among which histone deacetylases (HDACs), nuclear enzymes that, by modulating chromatin acetylation, regulate the balance between transcriptional activation and repression. In both skeletal muscles and nervous system, HDAC2 is one of the most represented. S-nitrosylation of HDAC2 results in its release from chromatin and consequent increase in histone acetylation and gene expression. Deregulation of NOS activity determines a dramatic reduction in histone acetylation and, hence, gene expression. This has been well demonstrated in dystrophic skeletal muscles lacking Dp427, but never investigated in neurons. By using mdx mice, a mouse model of DMD, and their wild type, this project aims at identifying: 1) changes in histone acetylation in different brain areas known to be affected in DMD; 2) evaluate the response of both skeletal muscles and neurons to class I HDACs specific inhibitor administration; 3) evaluate behavioral performances, before and after HDAC inhibition, by using tasks directed to specifically determine motor skills and different cognitive abilities.