Transposable Element Mobilization and Disrupted Translational Machinery in Down Syndrome

PROJECT SUMMARY This R01 proposal outlines a collaborative research initiative aimed at elucidating how mobilization of transposable elements (TEs) and alterations in mRNA translation disrupt the function of neural progenitor cells (NPCs) in Down Syndrome (DS). DS, or Trisomy 21, is the most common chromosomal cause of intellectual disability and is associated with impaired neurogenesis, leading to cortical maldevelopment in early life. Our data from the human prenatal brain has identified dramatic de-repression of TEs in DS cell subpopulations, which we have linked to activation of the antiviral innate immune system. Further, we have identified profound disruption in the mRNA translational machinery, including in many components of RNA granules. Based on this data, we first seek to map the TE landscape and cellular response in human induced pluripotent stem cell- derived NPCs, and test interventions to attenuate TE activation. Next, we will investigate changes to the translatome and proteome associated with DS, identifying novel TE-associated translation events. Finally, we hypothesize that DS NPCs exhibit significant alterations in the composition of subcellular cytoplasmic biomolecular condensates – RNA granules – that are critical mediators of mRNA metabolism and translation. We will map the protein and RNA composition of translation-associated condensates in DS NPCs and investigate how cytoplasmic phase separation dynamics are altered in DS. The knowledge derived from this research plan will not only enhance our understanding of the mechanisms through which DS impacts NPC function, but will also identify targetable pathways for reversing abnormal corticogenesis, offering potential avenues for intervention and prevention.