Neuroinfiammazione ed approcci terapeutici nella SLA

Abstract The aim of this thesis consists in highlighting the role of neuroinflammation in Amyotrophic Lateral Sclerosis (ALS) motor neuron (MN) cell death. First of all, I have described the general aspects of the disease (causes, pathogenesis and molecular bases). Then, by analyzing in detail three papers Ikiz et al. (2015, Cell Reports 12); Stamenkovic ́ et al. (2017, Neuroscience); Crisafulli et al., (2017 Springer Science), I focused on the key role of neuroinflammation in triggering MN death. Indeed, Ikiz and collaborators proposed an interesting in vitro ALS model, based on the culture of healthy ES-MNs in mutated (SOD1 G93A) astrocyte conditioned medium: such model perfectly resembles the regulatory machinery of the signal pathways involved in the disease and allowed the researchers to identify a set of regulatory genes driving MN degeneration, including 14 causal effector genes. In addition to the sophisticated molecular/computational analysis proposed by Ikiz and coll., I have then reported the morphological results of the Stamenkovic ́ work: the authors described the morphology and the distribution of glial cells in an ALS experimental model by analyzing immunofluorescence images of GFAP-positive astrocytes and IBA1-positive microglia in the brainstem and hippocampus, and by monitoring the accumulation of SOD1 protein, in correlation to the disease stages (presymptomatic and symptomatic). Finally, since it is evident that neuroinflammation contributes to ALS neurodegeneration and can represent an interesting therapeutic target, I have also presented some innovative therapeutic approaches, which target cells/molecules involved in the inflammatory process.