Jornal de Pesquisa do Cérebro

Endosomal Trafficking is disrupted in Neurodevelopmental Disorders

Abstract

Susan Cordero Romero, Ruvimbo Dzvurumi, Alexia Crockett, Alexandra Lombardo, Jhodi Webster, Samantha Hatcher, Alix Wagner, Diana Ghebrezadik, Asiya Abawari, Camryn Smith, Lauren Neal, Yommi Tadesse, Molly Beauchamp, Stacey B.B. Dutton and Jennifer L. Larimore

Endosomal trafficking has been implicated in several neurodevelopmental disorders including Rett Syndrome (RTT) and Schizophrenia (SZ). Endosomal proteins have been identified in genomic studies in both disorders, suggesting a common molecular mechanism. To characterize endosomal proteins in these disorders, we analyzed protein expression in the cortex and dentate gyrus of the hippocampus as well as in synaptosome preparations from whole-brain lysates. Immunofluorescent staining demonstrated alterations in key endosomal proteins in coronal brain sections from Mecp2 deficient mice and BLOC-1 deficient mice in the cortex and hippocampus. In addition, biochemical analysis of whole-brain homogenate and synaptosome fractions demonstrated an alteration in endosomal markers. Neurite outgrowth was also significantly decreased in PC12 cells lacking dysbindin and Mecp2. Lastly, to characterize alterations in endosomal trafficking, we used a pulse-chase assay in Mecp2 KD cells and observed altered kinetics of endosomal trafficking. Together, these data further characterize the role of endosomal trafficking mechanisms that underlie neurodevelopmental disorder pathogenesis, highlighting potential biomarkers or therapeutic targets for these disorders.