Dysregulation of Ribosomes and Focal Adhesions May Contribute to Altered Motility of Down Syndrome Fibroblasts

Down syndrome (DS) results from the trisomy of human chromosome 21. Common phenotypes of DS include intellectual disability, congenital heart defects, early-onset Alzheimer’s disease, and impaired wound healing. This study examines fibroblasts, cells that migrate to injury sites and contribute to the wound healing response, to provide insight into the delayed wound healing phenotype of DS. Two mechanisms that regulate fibroblast motility are adhesion and local translation. Focal adhesions (FA) are cellular structures that link the extracellular matrix to intracellular actin and provide forces necessary for cell migration. Local translation is the process by which mRNAs, ribosomes, and other translation factors are transported to specific subcellular regions. Following localization of mRNAs, molecular cues stimulate their local translation into protein. Previous research has shown deficits in fibroblast motility and local translation in DS. To better understand these deficits, vinculin, a key FA protein, was visualized using immunocytochemistry following a starve and stimulate paradigm in fibroblasts. This revealed that vinculin is dysregulated in the whole cell and at the leading edge in DS, which potentially contributes to migration deficits. Cells were then co-stained for ribosomal proteins (RPs), showing that RPL7α, a marker for the large ribosomal subunit, is upregulated in DS, while RPS6, a marker for the small subunit, is not. Unequal subunit pairing may waste cellular resources and alter translation, contributing to DS phenotypes. Furthermore, RPL7α was upregulated at the leading edge in DS, potentially impairing local translation and migration. Colocalization analysis of vinculin with RPs revealed no significant differences, suggesting that the ability of RPs to localize to FAs, an important process for cell migration, is not compromised in DS. Together, these findings show that ribosomes and FAs are impaired in DS, both in the whole cell and at the leading edge and may contribute to the migration and protein translation deficits in fibroblasts that underlie delayed wound healing. As many different cells, such as neurons, use similar mechanisms for directed movement, proliferation, and growth, expanding this work into other cell types will improve our understanding of a wide range of DS phenotypes.