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α-Dystroglycanopathy is a newly emerging subgroup of congenital muscular dystrophies (CMD) caused by the aberrant glycosylation of α-Dystroglycan (αDG). These glycanopathies can be caused by mutations in the gene encoding for αDG or in genes encoding for proteins involved in the αDG glycosylation pathway. αDG is a key element of muscle contraction. Indeed, it forms a molecular bridge connecting the internal actin cytoskeleton to the extracellular matrix (ECM), creating a physical anchorage. The ability of αDG to bind to ECM is due to a peculiar O-mannose–linked glycan structure that interacts with ECM proteins. Besides its role in muscle contraction, several fundamental functions have been ascribed to αDG in the nervous system, including its correct development and structural integrity. Indeed, in addition to muscular dystrophy, aberrant glycosylation of αDG associates with alterations in the central nervous system. Despite the crucial role of αDG, the molecular mechanism of its O-mannose–linked glycosylation pathway is almost unknown. Moreover, while the aberrant glycosylation of αDG explains CMD symptoms, it does not entirely account for all neurological disorders exhibited by patients. This indicates the presence of protein substrates for O-mannose-linked glycans other than αDG, and that its abnormal glycosylation may contribute to explain the complex spectrum of neurological defects associated with α-Dystroglycanopathies. The present proposal aims at fulfilling the above-described gaps to obtain a more precise understanding of the glycosylation of αDG, and in general of the O-mannose–linked glycosylation. The project will employ a multi-level approach that starts from the molecular details of the O-mannosyl transferase activity, enlarges the search field to the level of the cellular context and finally validates the obtained results in vivo.