Prevention of Lymphocyte Neurotoxic Effects by microRNA Delivery

Alessandra      Pulliero; Barbara      Marengo; Daniela      Fenoglio; Alessia      Parodi; Cristina      Cereda; Cinzia      Domenicotti; Simona      Orcesi; Jessica      Galli; Ivana      Olivieri; Gilberto      Filaci; Umberto      Balottin; Elisa      Fazzi; Alberto      Izzotti

doi:10.2174/22115366113029990010

Abstract

Aicardi Goutieres Syndrome (AGS) is characterized by mutations occurring in genes encoding RNAses. AGS mutations silence intracellular RNases resulting in an intracellular overload of short RNAs arresting the physiological production of microRNA required for brain development. MiR-219 is typically down-regulated in Aicardi Goutieres Syn-drome (AGS). The goal of this study is to investigate miR-219 role in protecting astrocytes co-cultured with AGS-mutated lymphocytes. These lymphocytes display neurotoxic properties due to the presence of AGS-mutation and to their activa-tion by interpheron-alpha (IFN). Obtained results provide the evidence that astrocytes transfected with microRNA-219 are protected from the neurotoxic action of AGS lymphocytes activated by IFN-alpha. In particular, the miR-219 transfection increased astrocyte viability, growth, and differentiation while decreasing cell necrosis and apoptosis. Thus, microRNA-219 transfection is a valuable strategy in order to confer resistance to astrocytes towards lymphocyte-induced neurotoxici-ty especially in the presence of IFN-alpha, whose levels are typically increased in the cerebrospinal fluid of AGS patients.

Keywords: Aicardi Goutieres Syndrome, interferon-alpha, lymphocytes, microRNA, miR-219 transfection, neurotoxicity.

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