Regulation Of Cell Signaling By Inter-Organeller Interaction In Neuronal And Non-Neuronal Cells: Effect On MicroRNA Mediated Gene Regulation

Abstract

Uponexposuretoamyloid-β oligomers(Aβ1–42), glialcellsstart expressingproinflammatorycytokines,despiteanincreaseinlevels of repressivemicroRNAs(miRNAs).Exploringthemechanismof thispotentialimmunityoftargetcytokinemRNAsagainstrepressive miRNAsinamyloid-β-exposedglialcells,wehaveidentifieddifferential compartmentalizationofrepressivemiRNAsinglialcellsthatexplains thisaberrantmiRNAfunction.InAβ1–42-treatedcells,whereastarget mRNAswerefoundtobeassociatedwithpolysomesattachedto endoplasmicreticulum(ER),themiRNAribonucleoproteincomplexes (miRNPs)werefoundtobepresentpredominantlywithendosomes thatfailedtorecycletoER-attachedpolysomes,preventingrepression of mRNAtargets.Aβ1–42 oligomers,bymaskingRab7aproteinson endosomalsurfaces,affectedRab7ainteractionwithRab-interacting lysosomalprotein(RILP),restrictingthelysosomaltargetingand recyclingofmiRNPs.RNA-processingbody(P-body)localizationof themiRNPswasfoundtobeenhancedinamyloid-β-treatedcellsas a consequenceofenhancedendosomalretentionofmiRNPs. Interestingly,depletionofP-bodycomponentspartlyrescuedthe miRNAfunctioninglialcellsexposedtoamyloid-β andrestrictedthe excesscytokineexpression