Brain inflammation in Duchenne muscular dystrophy: a possible contributor to the neurological comorbidities.

Proponente Francesca Grassi - Professore Ordinario
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Marta Morotti Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the gene encoding dystrophin, a protein critical for proper cytoskeletal scaffolding, which is expressed in muscle but also in the brain. Neuropsychiatric comorbidities are present in up to 30% of DMD patients, and in mdx mice (the mouse model of the disease), but the underlying mechanisms are not yet clear. In the general population, many of the co-morbid disorders are associated with neuroinflammation, which remains poorly investigated in relation to DMD. In the context of dystrophy, neuro-inflammatory processes could be due to both functional changes in the brain and secondary to the massive systemic inflammation that accompanies the disease. In the dystrophic brain inhibitory transmission is dampened, while possible abnormalities in astrocytes can boost the presence of glutamate, leading to excitotoxic damage. Peripherally, immune cells, stimulated by ongoing muscle damage, release cytokines that can reach the brain, also because the blood¿brain barrier is leaky in mdx mice Within the brain, proinflammatory cytokines activate microglia, which also produce cytokines. Thus, chronic systemic inflammation can extend to the brain. Aim of the present project is to examine the presence of inflammation in the brain of mdx mice, examining microglia phenotype, astrogliosis and concentration of inflammatory cytokines, as compared to wt animals. We will then examine whether blockade of Ca2+-activated K+ channels can reprogram microglia towards an anti-inflammatory phenotype, as in other disease, setting the stage for future studies on animal behaviour.


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