IL RUOLO DELL¿HUNTINGTINA NELLA FISIOLOGIA DEL DIFFERENZIAMENTO NEURONALE E NELLA PATOLOGIA

Huntingtin (htt) is the 3,144 amino acid protein whose mutation causes Huntington’s disease (HD). Mutant htt is toxic for brain neurons, but the mechanism leading to pathology is still far from being understood. Moreover, since loss of wild type (WT) htt contributes to pathogenesis, the study of htt’s role and the effect of its depletion, in the central nervous system becomes important. In this Thesis we analyse complementarily the role of WT and mutant htt in physiological and pathological conditions. In the first part, it is described a novel role of WT htt during neural development. This field is still quite unexplored, and, even if the function of protein has been largely described during post-natal life (when HD onset occurs), there are recent evidences that also normal development could be altered in htt depletion condition. Specifically it has been investigated the role of htt in establishment and maintenance of neuroepithelial apico-basal polarity and, as a result, in the regulation of neural progenitors cell fate decision. We demonstrate that htt, through cooperation with polarity protein aPKC, contributes to regulation of polarity mechanism during early neurogenesis. In the second part of the Thesis it is described the establishment of a human in vitro model of HD, thanks to somatic cell reprogramming technology. We report the generation of a series of induced pluripotent stem (iPS) cells derived from several patients. HD-iPS cells have the potential to be differentiated to the neuronal population that degenerate during disease progression, holding the identical genetic information of the donor. Starting also from rare homozygous patient, and demonstrating mutation related enhanced lysosomal activity, our work is the first that describes a cohort of HD-iPS cells and their phenotypical characterization.